LELAND    STANFORD    JUNIOR    UNIVERSITY    PUBLICATIONS 
UNIVERSITY    SERIES 


AN  INTRODUCTION  TO  THE  STUDY 

OF  THE  ENDOCRINE  GLANDS  AND 

INTERNAL  SECRETIONS 


LANE   MEDICAL   LECTURES,    1913 


BY 

SIR  EDWARD  SCHAFER 

REGIUS    PROFESSOR    OF    PHYSIOLOGY 
UNIVERSITY  OF  EDINBURGH 


STANFORD    UNIVERSITY,     CALIFORNIA 

PUBLISHED   BY   THE   UNIVERSITY 

1914 


-s  33 


CONTENTS. 


PAGE 

Lecture  I. — General  considerations  regarding  internal  secretions  and 

the  organs  which  furnish  them 5 

Lecture  II. — The  functions  of  the  thyroid  apparatus  .  .  .  .15 
Lecture  III. — The  functions  of  the  adrenal  apparatus  .  .  .  .34 
Lecture  IV. — The  pituitary  body  or  hypophysis  cerebri  ...  53 

Lecture  V. — The  internal  secretions  of  the  pineal  gland;  of  the  ali- 
mentary mucous  membrane;  of  the  pancreas;  and  of 
the  sexual  organs 79 


317030 


An  Introduction  to  the  Study  of  the  Endocrine 
Glands  and  Internal  Secretions 


Sir  Edward  Shafer 


LECTURE    I. 

GENERAL   CONSIDERATIONS   REGARDING   INTERNAL   SECRETIONS  AND   THE 
ORGANS  WHICH  FURNISH  THEM. 

Material  which  is  passed  into  the  blood  or  lymph  from  any  tissue  or 
cell  of  the  body  forms  what  has  been  termed  its  internal  secretion,  and 
organs  which  are  not  known  to  possess  any  other  function  than  that  of 
passing  such  material  into  the  blood  or  lymph  are  termed  internally 
secreting  or  endocrine  organs*  But  this  term  is  not  usually  extended 
to  organs  like  the  lymphatic  glands  of  which  the  material  production  is 
of  a  morphological  character,  although  until  recently  all  such  organs 
used  to  be  included  along  with  the  true  endocrine  glands,  the  functions 
of  which  were  at  that  time  unknown,  in  the  general  expression  of  ductless 
glands.  Under  this  last  term  were  comprised  not  only  the  thyroid  (to 
which  must  be  added  the  parathyroids),  the  suprarenal  capsules  or 
adrenals,  the  pituitary  body  or  hypophysis  cerebri,  and  the  pineal  gland 
or  epiphysis  cerebri,  to  which  we  now  commonly  ascribe  internally  se- 
creting functions,  but  also  the  thymus  gland,  the  tonsils,  lymph-glands 
and  lymph-follicles,  and  the  spleen;  with  these  the  bone-marrow  must 
also  be  associated.  Regarding  the  thymus  gland,  although  some  evidence 
has  been  adduced  that  it  may  yield  an  internal  secretion  to  the  blood 
which  exercises  a  specific  action  upon  the  functions  of  growth  and  de- 
velopment, especially  of  the  generative  organs,  it  appears  both  develop- 
mentally  and  structurally  to  present  undoubted  resemblance  to  the 
tonsils,  which  are  universally  allowed  to  be  structures  of  a  lymphatic 
nature,  and  most  of  its  cells  are  lymphocytic  in  character.  Some  have 
supposed  that  the  spleen  also  provides  an  internal  secretion  which  is 
destined  to  affect  the  quantity  of  the  pancreatic  juice.  But  the  proof 
of  the  existence  of  such  internally  secreting  functions  in  connexion 
with  these  lymphoid  organs  is  so  inferior  to  that  which  we  possess  re- 
garding the  thyroid,  parathyroids,  adrenals  and  pituitary,  and  even  the 


From  evSov,    within,  and  KpiW,  to  separate. 


6  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

pineal  gland,  that  we  may,  at  least  provisionally,  exclude  them  from  the 
class  of  organs  which  are  known  to  secrete  active  chemical  agents  into 
that  fluid  for  the  purpose  of  influencing  other  organs.  It  is  to  this 
latter  class  that  I  intend  to  restrict  my  remarks,  and  it  is  to  them  and 
them  alone  that  the  term  "endocrine  organ"  will  be  applied  in  these 
lectures. 

It  follows  from  what  has  just  been  said  that  by  the  expression  "en- 
docrine gland"  we  imply  an  organ  which  is  known  to  form  some  specific 
chemical  substance  within  its  cells  and  to  pass  this  directly  or  indirectly 
into  the  blood  stream.  The  substance  thus  formed  is  the  active  material 
of  its  secretion,  just  as  ptyalin  is  the  active  agent  of  the  salivary  secre- 
tion. But  while  in  the  case  of  the  salivary  glands  the  secretion  is  con- 
ducted by  a  duct  to  the  exterior,  in  the  case  of  the  ductless  glands  the 
secreted  material  remains  within  the  body  and  circulates  with  the  blood ; 
hence  the  term  "internal  secretion"  commonly  applied  to  it. 

The  expression  "internal  secretion"  was  originally  applied  in  a  sense  some- 
what different  from  that  in  which  it  is  now  used,  having  been  first  employed  by 
Claude  Bernard  to  describe  the  grape  sugar  which,  as  he  showed,  is  passed 
from  the  liver  cells  into  the  blood.  It  has  also  similarly  been  used  to  designate 
all  materials  which  are  contributed  to  the  blood  by  the  tissues.  In  this  man- 
ner the  carbon  dioxide  and  other  products  of  metabolism  which  are  taken  up 
*•"  *>-P  blood  in  its  passage  through  the  capillaries  or  are  received  by  it  through 
the  medium  of  the  lymph  stream  would  be  internal  secretions  and  every  tissue 
would  be  an  internally  secreting  structure.  It  is,  however,  convenient  to 
restrict  the  term  "endocrine"  to  substances  of  a  specific  nature  like  the  active 
chemical  agents  which  are  produced  by  the  ductless  glands,  and  this  is  the  sense 
in  which  the  expression  will  be  employed  in  these  lectures. 

But  it  is  proved  that  the  production  of  specific  chemical  agents  which 
are  passed  into  the  blood  and  carried  by  it  to  distant  structures  is  not 
confined  to  the  ductless  glands — that  an  active  internal  secretion  may  be 
produced  by  other  organs  than  these.  A  notable  example  is  met  with 
in  the  case  of  the  pancreas,  the  obvious  and  long  known  function  of 
which  is  the  production  and  excretion  into  the  intestine  of  pancreatic 
juice;  which,  by  virtue  of  the  ferments  it  contains,  is  the  most  active 
agent  in  the  digestion  of  food  stuffs  within  the  alimentary  canal.  In 
1889,  however,  it  was  shown  by  v.  Mering  and  Minkowski  that  the  pan- 
creas possesses  an  internal  secretory  function  which  is  of  even  greater 
importance  in  the  economy  than  its  long  recognized  external  secretory 
activity.  For  by  totally  removing  the  pancreas  in  animals  these  ob- 
servers proved  that  the  presence  of  the  gland  and  of  some  material 
yielded  by  this  gland  to  the  blood  is  essential  to  the  proper  utilisation  of 
carbohydrate  material  in  the  tissues,  so  that  if  the  organ  be  removed 


GENERAL    CONSIDERATIONS  7 

grape  sugar  is  no  longer  stored  in  the  liver,  and  little  by  little  split  up 
by  the  organism  into  simple  oxidisable  substances,  but  is  passed  out  from 
the  blood  in  which  it  is  in  excess  by  the  kidneys,  thus  producing  glyco- 
suria.  It  may  be  added  that  our  present  knowledge  of  the  etiology  of 
diabetes  is  mainly  based  on  these  observations. 

Now  it  is  known  that  the  pancreas  possesses,  besides  the  secreting 
aheoli  which  form  the  enlarged  and  blind  terminations  of  its  ducts,  a 
special  kind  of  secreting  cells  which  are  massed  together  into  islets  of 
irregular  shape  and  variable  number  and  size,  having  a  special  kind  of 
blood  supply.  These  islets,  which  were  first  described  as  a  distinct 
element  of  pancreatic  tissue  by  Langerhans,  have  been  originally  devel- 
oped from  and  may  retain  a  connexion  with  the  ducts  of  the  organ,  in 
this  respect  resembling  the  ordinary  alveoli.  But  in  the  course  of 
growth  they  have  lost  all  open  connexion  with  the  ducts;  their  cells 
have  acquired  specific  properties;  and  their  function  is  without  doubt 
different  from  the  ordinary  cells  of  the  gland.  With  some  show  of 
reason  the  special  internal  secreting  function  which  has  been  above  men- 
tioned has  been  ascribed  to  them,  and  in  support  of  this  it  may  be  stated 
that  in  many  if  not  most  cases  of  diabetes  these  cells  are  found  to  have 
undergone  degeneration.  They  in  fact  form  an  organ  within  an  organ, 
and  may  be  collectively  regarded  as  belonging  to  the  group  of  internally 
secreting  or  endocrine  organs. 

An  example  of  a  tissue  which  is  devoted  to  the  formation  of  both  an 
external  and  an  internal  secretion  is  found  in  the  epithelium  which  lines 
the  duodenum.  The  functions  of  this  epithelium  which  have  been  longest 
known  are  those  of  aiding  in  the  absorption  of  digested  food  materials 
and  of  helping  to  furnish  the  material  known  as  the  intestinal  juice. 
But  in  1902  it  was  discovered  by  Bayliss  and  Starling  that  if  an  extract 
of  the  duodenal  epithelium  is  boiled  with  dilute  hydrochloric  acid  and 
after  neutralization  is  injected  into  the  blood  stream  of  an  animal  a 
rapid  flow  of  pancreatic  juice  is  determined.  It  had  already  been  known 
that  the  gush  of  acid  gastric  juice  through  the  pylorus  or  the  painting  of 
the  mucous  membrane  of  the  duodenum  with  dilute  acid  would  determine 
a  flow  of  pancreatic  juice,  but  this  flow  had  been  supposed  to  be  brought 
about  as  a  reflex  act  by  excitation  of  a  local  nervous  mechanism  by  the 
acid.  The  observations  of  Bayliss  and  Starling  rendered  it  clear,  how- 
ever, that  this  is  not  the  correct  explanation  of  the  phenomenon;  but 
that  the  flow  must  rather  be  regarded  as  due  to  the  absorption  of  some 
internal  secretion  into  the  blood:  the  material  of  this  internal  secretion 
being  produced  in  an  inactive  form  by  the  epithelium  cells  and  becoming 
so  altered  by  the  dilute  acid  as  to  be  converted  into  an  agent  which,  after 


8  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

absorption  into  the  blood  stream,  excites  the  secreting  cells  of  the  pan- 
creas to  activity. 

To  the  active  substance  which  is  yielded  by  the  epithelium  cells  of  the 
duodenal  mucosa  the  name  secretine  was  given  by  Bayliss  and  Starling, 
whilst  they  termed  pro-secr&tine  the  inactive  material  contained  within 
the  cells  before  the  action  of  dilute  acid  upon  them.  The  active  material 
is  obviously  of  the  nature  of  an  internal  secretion;  it  appears,  however, 
not  to  be  produced  by  a  special  structure,  certainly  not  by  a  special 
organ ;  but  so  far  as  one  can  tell,  by  the  ordinary  cells  which  line  the 
mucosa  and  extend  into  its  glands. 

A  similar  but  not  identical  internal  secretion  has  been  shown  by  Ed- 
kins  to  be  produced  by  the  cells  of  the  mucous  membrane  of  the  pylori c 
end  of  the  stomach.  When  rendered  active  and  absorbed  into  the  blood 
this  secretion,  which  is  termed  gasirine  by  Edkins,  stimulates  not  the 
cells  of  the  pancreas  but  those  of  the  fundic  glands  of  the  stomach  itself. 

A  yet  more  remarkable  example  of  the  coincidence  of  external  and 
internal  secretory  functions  in  the  same  organ  is  supplied  by  the  genera- 
tive glands  (ovary  and  testicle).  It  has  been  known  from  time  imme- 
morial— the  experiment  is  repeated  daily  for  commercial  purposes  in 
thousands  of  animals,  and  is  still  practiced  upon  man  for  domestic  rea- 
sons in  certain  Oriental  countries — that  the  removal  of  the  generative 
glands  in  the  young  male  animal  usually  entirely  prevents  the  develop- 
ment of  the  accessory  generative  organs,  such  as  the  prostate,  and  of  the 
features  which  characterize  the  male  sex  externally.  These  changes  may 
be  prevented  by  successfully  grafting  a  testicle  in  the  castrated  animal. 

Again,  removal  of  the  ovaries  in  the  young  female  exerts  a  profound 
influence  over  the  organism  and  prevents  the  development  of  many  female 
characteristics.  In  some  cases,  even  in  the  adult,  removal  or  atrophy  of 
the  ovaries  has  been  noticed  to  lead  to  the  development  of  male  charac- 
ters. Instances  of  this  have  been  often  recorded  in  birds.  In  young 
mammals  removal  of  the  ovaries  is  followed  by  arrest  of  development  of 
the  uterus.  This  may  be  prevented  by  successfully  transplanting  the 
ovaries  or  by  grafting  an  ovary  from  another  animal  of  the  same  species 
into  the  peritoneum  or  elsewhere.  It  seems  clear,  therefore,  that  the 
result  of  removal  is  due  in  both  male  and  female  to  the  absence  of  the 
internal  secretion  of  the  generative  gland. 

THE  NATURE  AND  MODE  OF  ACTION  OF  THE  ACTIVE  PRINCIPLES  OF  THE 

INTERNAL  SECRETIONS. 

We  have  compared  the  active  materials  of  the  internal  secretions, 
which  are  formed  within  cells  and  passed  out  into  the  blood,  to  the  activo 


GENERAL,   CONSIDERATIONS  9 

agents  of  the  ordinary  secretions,  which  are  directed  on  the  exterior  by 
means  of  a  duct.  But  the  comparison  cannot  be  pressed.  In  the  case 
of  the  external  secretions,  the  active  agents  when  present  are  always  of 
the  nature  of  a  ferment.  They  belong  to  the  class  of  bodies  which  are 
known  as  enzymes.  The  conditions  and  modes  of  action  of  these  bodies 
are  for  the  most  part  familiar  to  the  biologist.  They  occur  not  only  in 
secretions  but  in  the  bioplasm  of  most  if  not  of  all  cells ;  indeed  the  chem- 
ical activity  of  the  cell  in  most  if  not  in  all  cases  depends  upon  its  con- 
tained enzymes.  Although  far  simpler  in  chemical  nature  than  the  bio- 
plasm by  which  they  are  produced,  and  in  no  sense  endowed  with  life, 
enzymes  are  very  probably  of  a  protein  nature,  and  they  are  readily 
destroyed  by  heat  in  presence  of  water.  The  active  materials  of  the 
internal  secretions,  on  the  other  hand,  are  for  the  most  part  not  rendered 
inactive  even  by  prolonged  boiling,  and  are  certainly  of  a  much  simpler 
chemical  constitution  than  enzymes.  They  are  dialyzable ;  and  although 
most  of  them  have  not  yet  been  isolated  in  a  crystalline  form,  due  prob- 
ably to  the  fact  that  it  is  difficult  to  obtain  them  free  from  impurities, 
some  of  them  have  been  so  obtained,  and  at  least  one — the  active  mate- 
rial of  the  adrenal  medulla — has  been  prepared  synthetically.  They  for 
the  most  part  act  readily  upon  the  cells  which  they  influence — at  least 
this  is  the  case  with  those  which  can  be  extracted  by  water  from  the 
organs  which  produce  them — and  the  extracts  often  exert  an  immediate 
effect  when  injected  into  the  blood;  whereas  it  is  usually  the  nature  of  an 
enzyme  to  operate  more  gradually.  The  action  of  the  principles  con- 
tained in  the  internal  secretions  and  capable  of  extraction  by  watery 
fluids  is  in  point  of  fact  not  very  dissimilar  from  that  produced  by  the 
active  principles  of  drugs,  especially  those  of  organic,  i.  e..  of  vegetable 
origin.  These  also  operate  by  immediate  chemical  action,  being  con- 
veyed to  the  parts  which  they  influence  in  solution  in  the  circulating 
blood.  As  with  drugs,  some  of  the  principles  contained  in  such  extracts 
of  the  endocrine  organs  act  by  stimulating  or  exciting  cell-f unctions : 
this  is  notably  the  case  with  the  principle  obtained  by  the  action  of  acid 
on  the  duodenal  epithelium.  Others  depress  or  inhibit  those  functions: 
an  example  of  this  is  met  with  in  extract  of  placenta,  which  when  injected 
into  the  bloodvessels  tends  to  inhibit  the  secretion  of  milk.  To  such 
stimulating  principles,  as  that  contained  in  the  extract  of  duodenum 
after  treatment  with  acids,  the  term  hormone  (from  op/mw,  to  stir 
up)  was  originally  applied  by  Starling,*  and  the  expression 
has  been  extended  to  include  the  active  principles  of  all  inter- 
nal secretions.  As  long  as  only  exciting  agents  were  known  there 


*Verhandl.  1. 


10  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

could  be  no  objection  to  this  extension  of  the  term,  but  since  agents  which 
produce  depression  or  cessation  of  function  have  been  shown  also  to  be 
produced  in  the  endocrine  glands — and  their  number  will  probably  be- 
come considerable  as  the  nature  of  the  internal  secretions  is  more  fully 
examined — it  is  advisable  to  employ  an  expression  which  will  discrimi- 
nate between  these  and  stimulating  agents.  I  propose  therefore  to  dis- 
tinguish the  action  of  the  depressants  from  that  of  the  excitants  by  the  use 
of  the  term  chalone  (from  ^aAao>,  to  make  slack).  A  chalone  may  there- 
fore be  defined  as  an  endocrine  product  which  inhibits  or  prevents  the 
activity  of  an  organ  or  tissue,  as  distinguished  from  a  hormone,  which 
excites  the  tissue  to  increased  activity.* 

Starling  does  not,  however,  confine  the  use  of  the  term  "hormone" 
to  organic  principles  of  an  endocrine  nature.  His  definition  is  much 
wider.  *  *  By  the  term  '  hormone, '  "  he  says,  ' '  I  understand  any  substance 
normally  produced  in  the  cells  of  some  part  of  the  body  and  carried  by 
the  blood  stream  to  distant  parts,  which  it  affects  for  the  good  of  the 
organism  as  a  whole."  (Proc.  Roy.  Soc.  Med.,  Vol.  vii.,  Therap.  and 
Pharm.  Sect.,  p.  29).  He  then  proceeds  to  give  as  examples  of  hormones, 
secretine,  adrenine,  and  carbonic  acid — the  last,  which  is  produced  by  the 
tissues  in  general  and  more  especially  by  muscular  tissue,  stimulating  the 
respiratory  centre  to  activity.  Obviously  this  definition  would  include 
most  substances  normally  present  in  the  blood,  such  as  water,  urea,  glu- 
cose and  inorganic  salts,  which  are  produced  in  various  parts  of  the  body 
and  affect  distant  organs  such  as  the  kidneys :  indeed  it  may  be  supposed 
that  all  substances  in  the  blood  will,  when  we  know  more  about  their 
history,  come  into  the  definition.  The  expression  hormone  has  not  been 
hitherto  employed  by  physiologists  and  clinicians  in  this  extended  sense; 
the  term  has  invariably  been  restricted  to  the  active  organic  principles  of 
the  internal  secretions.  But  it  will  be  best  to  employ  the  term  hormone 
in  the  sense  in  which  it  is  used  by  its  inventor,  i.  e.,  to  denote  any  sub- 
stance in  the  blood  which  excites  cells  of  the  body  to  activity,  and  to 


*The  original  expression  employed  by  Bayliss  and  Starling  ( Journ.  Physiol.) 
in  their  paper  on  secretine  was  "chemical  messenger."  This  is  more  appropriate 
as  a  general  term  than  "hormone"  because  it  includes  all  chemical  agents  which 
produce  an  effect  at  a  distance,  whether  such  effect  be  excitatory  or  inhibitory. 
If,  in  place  of  "hormone,"  Starling  had  selected  the  expression  "hermone" 
('Ep^s,  Mercury),  the  difficulty  which  is  caused  by  the  use  of  the  term  "hor- 
mone," which  implies  excitation,  for  agents  which  act  in  exactly  the  contrary 
manner,  would  not  be  felt.  Biedl  distinguishes  "erregende  Hormonen"  from 
"hemmende  Hormonen,"  i.  e.,  excitants  which  excite,  from  excitants  which  pre- 
vent excitation.  It  is  true  that  he  regards  the  one  class  as  exciting  katalobic 
changes  and  the  other  as  exciting  anbolic  changes,  but  this  is  purely  theoretical, 
and  in  many  cases  it  is  improbable  that  this  is  their  mode  of  action. 


GENERAL   CONSIDERATIONS  11 

denote  by  a  special  term  those  specific  substances  which  are  produced  by 
the  organs  of  internal  secretion  for  the  purpose  of  either  exciting  or  re- 
straining the  activity  of  distant  organs.  Since  the  most  characteristic 
feature  of  the  action  of  these  substances  is  the  resemblance  to  the  action 
of  drugs,  such  as  the  vegetable  alkaloids,  I  propose  to  employ  for  these 
specific  substances  the  general  title  "autaeoid  substances,"  or,  simply, 
"autacoids"  (dwos,  self,  and  a*os,  a  medicinal  agent  or  remedy).  I 
would  accordingly  define  an  autacoid  as  a  specific  organic  substance 
formed  by  the  cells  of  one  organ  and  passed  from  them  into  the  circu- 
lating fluid  to  produce  effects  upon  other  organs  similar  to  those  produced 
by  drugs.  Such  effects  are  either  in  the  direction  of  excitation,  in  which 
case  the  endocrine  substances  producing  them  may  be  termed  excitatory 
autacoids  and  would  come  under  the  expression  "hormones,"  or  in  the 
direction  of  restraint  or  inhibition,  in  which  case  they  may  be  termed 
restraining  or  inhibiting  autacoids  and  be  classed  as  "chalones."  And 
the  action  of  an  autacoid  may  be  described  as  hormonic  or  chalonic,  ac- 
cording to  the  kind  of  effect  it  produces. 

Some  autacoid  substances  appear  to  produce  opposite  results  in  differ- 
ent parts  of  the  body.  Thus  the  adrenine  of  the  suprarenal  medulla 
causes  contraction  of  the  plain  muscle  of  the  bloodvessels  and  inhibition 
of  that  of  the  intestines.  But  in  both  cases  the  action  may  be  regarded 
as  that  of  a  hormone  or  exciting  agent,  for  both  effects  are  produced  by 
stimulating  the  end  substance  of  the  sympathetic  nerves.  In  extreme 
dilution  (1  to  1,000,000  or  less)  in  mammals,  and  in  a  less  dilute  form  in 
birds,  adrenine  causes  inhibition  instead  of  contraction  of  the  muscle  of 
the  bloodvessels.  But  this  again  may  be  produced  by  excitation  of  in- 
hibitory nerve  fibres  by  the  more  dilute  solution,  and  if  so  the  action 
would  still  be  hormonic.  Nevertheless,  the  possibility  of  the  same  auta- 
coid substance  acting  under  some  circumstances  as  a  hormone  or  excitant 
and  under  other  circumstances  as  a  chalone  or  depressant  must  be  borne 
in  mind.  This  indeed  serves  to  illustrate  the  drug-like  nature  of  these 
principles,  for  such  inversion  of  action  under  different  circumstances  is 
known  to  occur  with  some  alkaloids. 

GROUPINGS  OF  THE  CHIEF  ENDOCRINE  GLANDS. 

The  principal  ductless  or  endocrine  glands  can  be  grouped  under  the 
three  main  heads  of  thyroid  apparatus,  suprarenal  apparatus  and  pitui- 
tary or  hypophysial  apparatus.  With  regard  to  these  groups,  it  is  note- 
worthy that  each  of  the  organs  forming  the  group  is  compounded  of  two 
distinct,  but  usually  closely  intergrown  parts.  Thus  the  thyroid  appa- 
ratus is  composed  of  thyroid  proper  and  parathyroids;  the  suprarenal  of 
cortical  and  medullary  fine  tissues;  the  pituitary  of  epithelial  and 


12  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

epithelio-neural  portions.  And  in  each  case  the  functions  of  the  two 
portions,  so  far  as  is  known,  appear  to  be  in  no  way  related,  difficult  as  it 
is  to  believe  that  tissues  so  closely  connected  anatomically  should  have 
no  sort  of  functional  connexion.  The  close  anatomical  connexion  is, 
however,  sometimes  absent,  as  with  those  parathyroids  which  are  alto- 
gether detached  from  the  thyroid  and  as  with  the  paired  bodies  and  the 
interrenal  body  of  the  Elasmobranch  fishes.  A  close  anatomical  rela- 
tionship without  any  known  functional  bearing  is,  however,  not  without 
examples  in  other  organs,  e.  g.,  in  the  frog  there  exists  a  very  intimate 
anatomical  connexion  of  the  suprarenal  with  the  kidney,  although  there 
is  no  reason  to  believe  that  any  special  functional  relationship  obtains 
between  the  two. 

It  is  further  noticeable  that  in  each  of  the  above  groups  one  of  the  two 
parts  has  a  more  evident  and  in  a  sense  a  more  active  function  than  the 
other.  Thus  the  removal  of  the  parathyroids  occasions  symptoms  which 
are  far  more  acute  than  those  produced  by  the  corresponding  operation 
on  the  thyroid  alone.  And  extracts  of  the  medullary  substance  of  the 
adrenals  and  of  the  posterior  or  epithelio-neural  part  of  the  pituitary 
have  an  immediate  and 'striking  effect  on  various  tissues  and  organs  when 
injected  into  the  bloodvessels,  whilst  similar  extracts  of  the  cortical  sub- 
stance of  the  adrenals  or  of  the  anterior  or  epithelial  part  of  the  pituitary 
are  without  any  obvious  action.  There  is,  however,  in  the  case  of  the 
thyroid,  direct  experimental  as  well  as  clinical  evidence,  and,  in  the  case 
of  the  suprarenal  capsules  and  pituitary,  the  testimony  of  much  clinical 
observation  to  furnish  reason  for  the  belief  that  the  portions  of  these 
glands  extracts  which  are  inactive  when  injected  into  the  blood  may 
exercise,  if  a  slower,  yet  a  no  less  potent  influence  upon  the  organism 
than  the  portion  the  activity  of  which  can  be  demonstrated  by  intraven- 
ous injection. 

METHODS  OF  DETERMINING  THE  FUNCTIONS  OF  THE  DUCTLESS  GLANDS. 

Two  general  methods  are  employed  for  this  purpose,  the  one  being 
the  observation  of  the  changes  which  result  from  partial  or  complete 
surgical  removal  of  the  organ  in  man  and  animals  or  its  destruction  by 
disease,  and  the  other,  observation  of  the  changes  which  result  from  the 
administration  of  watery  or  saline  extracts  prepared  from  the  organ.  As 
has  been  already  stated,  the  active  principles  of  the  endocrine  glands 
are  not  destroyed  by  boiling  with  water  or  Ringer's  solution,  at  least  for 
a  short  time.  Advantage  is  taken  of  this  fact  to  prepare  extracts  which 
are  free  or  almost  free  from  protein  or  nucleo-protein,  since  the  intro- 
duction of  these  substances  into  the  blood  might  tend  to  mask  the  effect 
of  the  autacoid  which  is  being  tested.  In  this  way  solutions  may  be  pre- 


GENERAL   CONSIDERATIONS  13 

pared,  and  kept,  after  sterilization,  in  hermetically  sealed  receptacles 
almost  indefinitely.  Preserved  in  the  dry  condition  also  the  autacoids 
appear  to  undergo  no  diminution  of  their  activity.  In  these  particulars 
animal  autacoids  resemble  extracts  of  plants  containing  active  medicinal 
principles  of  an  organic  nature,  with  the  action  of  which,  as  has  already 
been  indicated,  the  effects  they  produce  bear  a  close  comparison. 

The  extracts  can  be  administered  by  the  mouth,  or  by  subcutaneous, 
or  intramuscular,  or  intraserous,  or  intravenous  injection.  The  last  men- 
tioned method,  viz.,  injection  into  a  vein,  being  the  most  direct,  is  the 
one  generally  resorted  to  for  the  determination  of  their  action.  It  was 
first  employed  to  investigate  the  physiological  action  of  such  extracts  in 
1894,  and  led  immediately  to  the  discovery  of  the  bloodpressure-raising 
principles  of  the  suprarenal  capsules  and  of  the  pituitary  body. 

Administration  by  the  mouth. — This  is  well  known  to  be  effective  in 
the  case  of  the  thyroid  and  the  fact  is  taken  advantage  of  in  cases  of 
hypothyroidism  such  as  occurs  in  endemic  goitre,  cretinism  and  myxce- 
dema.  On  the  other  hand,  thyroid  juice  or  the  substance  of  the  gland 
given  freely  with  the  food  in  normal  individuals  produces  symptoms 
which  are  interpreted  as  due  to  excess  of  the  thyroid  autacoids  in  the 
blood.  With  smaller  doses  certain  effects  are  produced  upon  metabolism, 
including  an  increase  of  N-secretion  and  an  increase  of  O2  intake  and  of 
C02  excretion,  with  the  reduction  of  body  fat.  Buccal  administration  is 
stated  by  Gushing  to  yield  good  results  with  pituitary  extracts  or  pituitary 
gland  substance  in  cases  of  hypopituitarism,  although  in  normal  in- 
dividuals no  effect  is  apparent.  Buccal  administration  of  suprarenal 
extract  also  givesjittle  result  in  normal  individuals,  but  both  in  Addi- 
son's  disease  and  in  certain  other  affections  beneficial  effects  have  fre- 
quently been  recorded  when  the  extract  has  been  thus  administered. 

Administration  by  subcutaneous  or  intramuscular  injection. — As  with 
drugs  the  effects  of  administering  the  animal  autacoids  by  hypodermic 
injection  are  usually  more  rapid  and  more  marked  than  with  buccal 
administration.  But  in  some  cases  the  difference  is  not  very  striking  so 
far  as  immediate  results  are  concerned.  If,  however,  extract  of  the 
medulla  of  the  suprarenals  or  of  the  posterior  lobe  of  the  pituitary  body 
are  administered  by  intramuscular  injection — absorption  being  pro- 
moted by  gentle  massage — they  rapidly  cause  their  characteristic  effects 
(Meltzer  and  Auer).  Probably  the  reason  why  these  extracts  when  given 
by  hypodermic  injection  produce  little  general  result — although  the  local 
effects  in  causing  vasoconstriction  may  be  very  marked — is  that  the 
autacoid  is  rapidly  destroyed  in  the  body;  so  that  when  absorbed  slowly 
it  is  got  rid  of  before  any  excess  is  able  to  accumulate  in  the  blood.  This 


14  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

applies  only  to  moderate  doses  and  to  the  immediate  effects.  Secondary 
effects  may  be  seen  with  large  doses,  and  these  may  be  of  a  marked 
character. 

Intravenous  injection.  The  immediate  effects — if  any — of  the  ani- 
mal autacoids  are,  as  with  drugs,  unfailingly  exhibited  as  the  result  of 
the  injection  into  a  vein  of  Ae  extracts  containing  them.  In  this  man- 
ner can  be  shown  the  action  of  extract  of  thyroid  in  causing  a  marked 
but  evanescent  depression  of  the  bloodpressure  and  in  affecting  the  excita- 
bility of  the  depressor  nerve:  the  various  effects  of  extract  of  supra- 
renal medulla;  such  as  contraction  of  bloodvessels  with  raising  of  blood- 
pressure,  acceleration  of  the  heart,  sometimes  preceded  or  followed  by 
inhibition,  flow  of  saliva,  erection  of  hairs,  dilatation  of  pupils,  retraction 
of  third  eyelids,  and  protrusion  of  eyeballs,  contraction  of  uterus,  vas 
deferens  and  seminal  vesicles,  inhibition  of  gastric  and  intestinal  move- 
ments and  of  the  bladder:  as  well  as  those  produced  by  extracts  of  the 
posterior  lobe  of  the  pituitary,  such  as  contraction  of  the  bloodvessels 
with  slowing  of  the  heart,  increase  of  secretion  from  the  kidneys,  outflow 
of  milk  from  the  mammary  gland,  contraction  of  the  uterus,  of  the  intes- 
tines, and  of  plain  muscle  in  general. 

A  caution  must  here  be  entered  against  the  too  hasty  conclusion  that  a 
particular  effect  obtained  in  injecting  an  organ  extract  is  a  specific  effect  due 
to  the  autacoid  substance.  Especially  is  this  warning  necessary  in  experiments 
inr  which  the  bloodpressure  is  employed  as  the  gauge  of  activity.  For  there  are 
few  organs  which  yield  extracts  that  are  absolutely  inert  when  tested  by  intrav- 
enous injection.  This  applies  to  many  glandular  and  lymphatic  structures, 
extracts  of  which  cause  generally  a  rapid  fall  of  bloodpressure,  which  is,  how- 
ever, usually  speedily  recovered  from,  but  sometimes — as  with  kidney  extracts — 
a  more  or  less  distinct  and  prolonged  rise.  The  depressor  effect  seems  often 
to  be  dependent  upon  the  presence  of  nucleo-protein  in  the  extract  and  is  usu- 
ally greater  in  proportion  to  the  number  of  nucleated  cells  which  the  organ 
contains.  Sometimes  it  may  be  due  to  the  presence  of  choline.  The  pressor 
effect  sometimes  seen  is  also  probably  not  specific.  Whatever  produces  it  is  not 
of  the  nature  of  ordinary  autacoids;  it  differs  from  these  in  being  destroyed  by 
boiling. 

Extracts  of  various  animal  tissues — especially  if  unboiled — are  liable  to 
produce  intra vascular  clotting.  If  this  be  general,  instant  death  is  the  result; 
if  localized,  it  may  manifest  itself  by  serious  interference  with  the  functions  of 
the  nervous  system  or  of  other  organs:  and  the  result  of  such  injection  might 
erroneously  be  set  down  to  a  specific  action  of  the  extract  injected,  although 
it  would  obviously  only  represent  the  result  of  an  accident.  A  similar  caution 
applies,  although  in  a  minor  degree  and  for  a  different  reason,  to  effects 
obtained  as  the  result  of  buccal  and  hypodermic  administration  of  animal- 
extracts,  for  such  effects — especially  differences  caused  by  different  extracts — 
may  (unless  they  can  be  otherwise  proved  to  be  specific)  be  produced  by 
variations  in  amount  of  such  organic  substances  as  nucleo-protein  or  other 
nutritive  materials  which  may  affect  growth  and  metabolism,  when  added  to 
the  ordinary  diet  of  animals. 


THE  THYROID  APPARATUS  15 

LECTURE  II. 
THE  FUNCTIONS  OF  THE  THYROID  APPARATUS. 

This  apparatus  consists  (1)  of  the  thyroid  proper,  in  the  form  of  two 
lobes  (generally  united  in  man  by  an  isthmus  over  the  trachea)  situated 
on  either  side  o^the  larynx  and  windpipe,  and  (2)  of  the  parathyroids; 
two  on  each  side:  one — the  superior  (parathyroid  IV),  which  is  usually 
in  contact  with  the  corresponding  lobe  of  the  thyroid  near  its  dorsal 
aspect*,  whilst  the  other — the  inferior  (parathyroid  III),  lies  either  in 
contact  with  the  corresponding  lobe  of  the  thyroid  at  its  ventral  aspect 
or  is  removed  a  greater  or  less  distance  from  it,  sometimes  as  low  down 
as  the  thymus. 

The  thyroid  may  contain  embedded  in  its  substance  a  portion  of 
tissue  resembling  that  of  the  thymus  gland,  and,  like  that,  containing 
lymphocytes  and  corpuscles  of  Hassall.  Such  portion  of  thymus  tissue  is 
developed  from  the  same  branchial  cleft  (IV)  as  the  superior  parathyroid, 
whereas  the  main  thymus  is  developed  from  cleft  III.  Accessory  thy- 
roids, usually  quite  small,  occasionally  occur  in  the  tissues  of  the  neck 
and  in  the  anterior  mediastimum. 

STRUCTURE  AND  DEVELOPMENT  OF  THYROID. 

The  thyroid  proper  is  an  organ  consisting  of  small  closed  vesicles  of 
varying  size  and  shape,  but  for  the  most  part  spheroidal.  Each  vesici^ 
is  lined  by  epithelium  which  is  usually  cubical;  but  the  cells  may  be 
columnar  or  flattened  in  accordance  with  the  state  of  distension  of  the 
vesicles.  There  is  no  definite  basement  membrane  separating  the  epithe- 
lium from  the  connective  tissue  and  bloodvessels.  The  vesicles  are  gen- 
erally filled  by  the  so-called  "colloid,"  a  viscid  fluid  in  the  fresh  organ, 
which  is  coagulated  into  a  solid  substance  by  fixative  reagents.  The  inter- 
vesicular  substance  is  areolar  tissue,  containing  in  parts  many  small  cells. 
Some  of  these  are  lymphocytes  whilst  others  are  not  unlike  those  of  the 
parathyroids,  although  the  identity  has  not  been  established.  There  are 
also  very  numerous  bloodvessels,  the  thyroid  being  one  of  the  most  vas- 
cular organs  in  the  body,  receiving  in  proportion  to  its  size  more  than 
five  times  as  much  blood  as  the  kidneys.  The  capillaries  penetrate  as  far 
as  the  vesicular  epithelium  with  which  they  come  into  immediate  contact. 
There  are  numerous  lymphatics  within  the  organ,  and  ' '  colloid ' '  like  that 
of  the  vesicles  is  said  to  be  occasionally  seen  within  them.  The  gland 
receives  nerves  from  the  sympathetic  and  from  the  vagus  through  the 


*In  some  animals  this  parathyroid  is  embedded  in  the  substance  of  the  lobe. 


16  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

superior  and  .inferior  laryngeal :  the  nerves  are  distributed  both  to  the 
bloodvessels  and  to  the  secreting  epithelium. 

The  vesicles  of  the  thyroid  do  not  always  present  the  appearance 
above  described.  Sometimes  they  are  irregular,  with  projections  of 
the  wall  into  their  interior,  and  are  lined  with  pronouncedly  columnar 
epithelium  cells.  In  these  circumstances  there  is  usually  little  or  none 
of  the  typical  colloid  material  in  the  vesicles — although  the  appearance 
of  the  epithelium  is  that  of  marked  secretory  activity.  It  may  be 
inferred  that  the  secreted  material  finds  in  these  cases  a  ready  exit 
from  the  vesicles  and  thus  fails  to  accumulate  within  them :  it  is  possi- 
ble that  it  may  also  be  different  in  consistence  and  quality.  So  far  as 
can  be  ascertained  these  differences  of  appearance  are  seen  in  animals 
which  are  otherwise  normal.  A  glandular  structure  of  this  type,  but 
even  more  pronounced,  is  noticeable  in  the  thyroid  in  cases  of  ex- 
ophthalmic goitre  in  man.  It  is  usually  interpreted  as  indicative  of  the 
production  of  excess  of  secretion  (hyperthyroidism).  The  epithelium 
cells  of  the  vesicles  contain  fatty  granules  which,  according  to  Erdheim, 
increase  in  number  with  age:  they  are  most  numerous  near  the  free 
border.  The  "colloid"  is  insoluble  in  alcohol,  water,  or  either:  when 
coagulated  it  is  readily  stained  by  eosin,  less  easily  by  haematoxylin. 
In  fixed  sections  it  often  appears  to  be  shrunken  away  from  the 
epithelium.  It  is  believed  to  be  formed  from  granules  which  are 
produced  within  the  cells  and  which  become  changed  and  dissolved 
on  extrusion.  Doubtless  it  contains  the  active  principles  of  the  se- 
cretion and  probably  forms  a  storehouse  whence  they  can  be  extracted 
as  required  by  the  organism. 

The  "colloid"  of  the  thyroid  appears  always  to  contain  iodine. 
It  is  true  that  cases  have  been  recorded  both  in  man  and  animals  in 
which  a  negative  result  has  been  obtained  on  analysis,  but  according  to 
A.  T.  Cameron,  this  is  probably  due  to  the  employment  of  methods  of 
detection  less  sensitive  than  those  now  used. 

The  thyroid  is  found  in  all  Vertebrata  from  Amphioxus  upwards. 
It  is  originally  developed  in  the  same  way  as  an  ordinary  secreting 
gland  by  a  median  outgrowth  from  the  entoderm  lining  the  floor  of 
the  pharynx  at  a  level  between  the  first  and  second  branchial  arches. 
It  appears  very  early  and  grows  backwards  as  a  solid  column  of  cells, 
bifurcating  at  the  upper  end  of  the  trachea  into  two  lateral  portions. 
The  solid  column  is  hollowed  out  into  a  duct  (ductus  thyreoglossus), 
which  presently  becomes  obliterated,  usually  completely;  its  original 
opening  remains  throughout  life  as  the  foramen  caecum  at  the  back 
of  the  tongue.  The  lateral  parts  into  which  the  caudal  end  divides 


THE   THYROID  APPARATUS  17 

branch  again  and  again  to  form  a  system  of  hollow  epithelium-lined 
tubes,  and  later  these  become  cut  up  into  the  closed  vesicles  which  are 
characteristic  of  the  gland.  In  mammals  they  are  joined  by  outgrowths 
from  the  ventral  wall  of  the  pharynx  on  each  side  behind  the  last 
branchial  cleft  (post-branchial  bodies)  ;  these  accordingly  contribute 
to  the  formation  of  the  organ,  but  to  a  very  different  degree  in  dif- 
ferent species  of  animals. 

STRUCTURE  AND  DEVELOPMENT  OF  PARATHYROIDS. 

The  parathyroids  are  four  minute  organs  each  averaging  6  mm. 
in  length,  and  3  to  4  mm.  broad,  and  weighing  0.03  gramme  (half  a 
grain).  Sometimes  there  are  more  than  four,  rarely  less.  As  already 
stated,  one  or  more  may  occur  altogether  detached  from  the  thyroid, 
but  usually  in  man  they  are  closely  attached  to  it:  one  may  even  be 
embedded  in  its  substance.  They  were  described  by  Sandstrom  in  1888. 
Their  physiological  independence  and  distinction  from  the  thyroid 
proper  was  recognised  by  Gley  in  1891  and  confirmed  by  Vassali  and 
Generali  in  1896,  but  is  not  fully  accepted  by  Vincent  and  a  few 
other  authorities. 

Each  parathyroid  is  a  mass  of  polygonal  epithelium-like  cells, 
arranged  in  strands  or  trabeculae  with  numerous  sinus-like  capillaries 
running  between  or  around  them.  There  is  a  capsule  of  areolar  tissue 
sending  in  processes  to  join  the  interstitial  tissue  of  the  organ:  plain 
muscle  cells  have  been  described  in  this:  it  may  also  contain  fat-cells. 
Besides  the  ordinary  cells  of  the  gland — which  are  stained  with  dif- 
ficulty by  most  dyes — others  occur  which  contain  oxyphil  granules, 
staining  intensely  with  eosin  (Welsh)  :  these  only  appear  after  the 
tenth  year  in  man.  Whether  they  represent  a  functional  stage  of  the 
ordinary  cells  or  not  is  uncertain.  Both  kinds  of  cells  contain  fatty 
granules;  glycogen  has  also  been  detected  in  them. 

Vesicles  containing  colloid  material  similar  to  those  of  the  thyroid 
but  usually  smaller  are  frequently  found  in  the  parathyroids.  They 
usually  increase  in  number  with  age,  and  occasionally  the  colloid  is 
found  between  the  cells,  not  enclosed  within  a  vesicle.  Whether  it  is 
of  the  same  chemical  nature  as  that  of  the  thyroid  is  not  established. 
But  it  is  noteworthy  that  after  complete  removal  of  the  thyroid  with 
those  parathyroids  which  are  embedded  in  it,  the  colloid-containing 
vesicles  of  the  parathyroids  which  have  been  left  were  found  by  Vincent 
and  Jolly  to  be  increased  both  in  number  and  size.  This  observation 
has  been  confirmed  by  Halpenny  and  Thompson,  who  have  found  that 


18  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

if  the  animal  survives  a  sufficient  time  these  vesicles  become  large  and 
irregular  and  present  a  close  resemblance  to  those  of  a  thyroid  in 
superactivity,  as  in  exophthalmic  goitre.  The  same  observers  found 
that  after  removal  of  all  the  parathyroids  the  thyroid  tissue  itself  may 
take  on  a  similar  appearance,  with  large  and  irregular  vesicles.  In 
this  case  there  is  also  seen  a  multiplication  of  intervesicular  cells,  and 
these  appear  to  be  of  the  same  nature  as  the  cells  of  the  parathyroids. 
The  conclusion  is  that  the  tissues  of  the  two  organs  are  largely  inter- 
mixed, at  least  in  birds  and  mammals,  although  in  lower  Vertebrates 
Mrs.  Thompson  found  the  two  to  be  completely  separate  both  develop- 
mentally  and  structurally.  Biedl  has  made  a  similar  observation  of 
the  development  of  colloid-containing  vesicles  in  the  parathyroid  in  a 
case  of  atrophy  of  the  thyroid  in  man. 

The  nerves  of  the  parathyroids,  like  those  of  the  thyroids,  pass 
both  to  the  vessels  and  to  the  secreting  cells.  Some  evidence  has  been 
adducd  by  Asher  and  by  Edwards  which  seems  to  show  that  the  cell- 
activity  is  controlled  by  the  nervous  system. 

The  parathyroids  are  developed  from  outgrowths  of  the  Illrd  and 
IVth  visceral  clefts  on  either  side:  from  the  same  clefts  the  rudiments 
of  the  thymus  are  also  derived;  occasionally,  as  already  mentioned,  one 
or  more  outgrowths  from  the  thymus  rudiments  pass  into  the  thyroid. 
On  the  other  hand  parathyroid  and  even  thyroid  tissue  occasionally 
occurs  within  the  thymus:  in  some  animals,  e.  g.  the  sheep,  con- 
stantly. 

EFFECTS    OF    REMOVAL    OR    DESTRUCTION    OF    THE    THYROPARATHYROID 

APPARATUS. 

Surgical  or  experimental  removal  of  this  apparatus  (a)  may  be 
complete;  or  (b)  may  be  confined  to  the  thyroid,  with  or  without 
those  parathyroids  which  are  embedded  in  its  substance,  the  other  two 
being  left;  or  (c)  may  involve  only  the  parathyroids,  most  of  the  thy- 
roid itself  being  left.  The  results  vary  (1)  with  the  nature  and  com- 
pleteness of  the  operation,  (2)  with  the  species  of  animal,  (3)  with 
the  age  of  the  animal. 

Effects  of  parathyroidectomy. — If  the  operation  is  complete,  i.  e.  if 
it  includes  all  four  parathyroids — most  animals  die  as  the  result  of 
the  removal;  some  within  a  few  days,  others  within  a  few  weeks.  The 
most  acute  symptoms  are  exhibited  by  carnivora  such  as  dogs,  cats, 
foxes  and  wolves  (Vincent)  and  the  young  of  herbivora  (v.  Eiselsberg, 
Sutherland  Simpson)  and  are  of  a  nervous  nature.  For  the  first  day  or 


THE   THYROID  APPARATUS  19 

two  there  are  no  symptoms,  other  than  some  loss  of  appetite.  There 
then  supervenes  marked  exaltation  of  reflexes,  which  leads  to  the  oc- 
currence from  time  to  time  of  fibrillar  contractions  of  muscles  and  later 
cramp-like  and  clonic  contractions,  and  eventually  convulsive  fits;  these 
may  be  of  considerable  violence  and  alternate  with  intervals  of  de- 
pression. The  body  temperature  may  rise  two  or  three  degrees  (centi- 
grade) during  the  fit.  The  paroxysms  are  usually  accompanied  by 
rapid  gasping  respirations  which  may  be  synchronous  with  the  heart- 
beats; sometimes  by  vomiting  and  diarrhoea.  Death  may  occur  within 
a  few  days  or  the  affection  may  last  a  long  time  and  spontaneous  re- 
covery may  occur.  The  syndrome  is  usually  spoken  of  as  "tetany" 
(tetania  paratkyreopriva) ;  which  is  in  no  way  synonymous  with 
"tetanus."  The  fits  are  sometimes  frequent  but  more  often  occur  at 
long  intervals;  the  animal,  if  it  fails  to  recover  from  the  effects  of 
the  removal,  usually  succumbs  during  a  convulsion. 

Tetany  is  without  doubt  due  to  the  loss  of  the  parathyroids,  for  it 
will  occur  when  these  alone  are  removed.  It  may  take  an  acute  or  a 
chronic  form  and  it  varies  greatly  in  severity.  The  symptoms  may  re- 
main latent  for  a  considerable  time  and  only  show  themselves  as  the 
result  of  some  unusual  condition  such  as  pregnancy.  The  effect  is  on 
the  motor  neurones,  for  Horsley  and  Lanz  state  that  it  is  not  influenced 
by  ablation  of  cerebral  cortex;  nor,  according  to  Mustard,  by  section 
of  dorsal  roots.  After  spinal  transection  it  disappears  below  the  level 
of  the  lesion,  but  the  hind  limbs  may  show  rhythmic  movements.  In 
many  cases  it  is  relieved  by  administration  of  thyroid  substance:  it  is 
uncertain  if  this  result  is  due  to  included  parathyroid  alone.  When 
tetany  is  produced  by  total  extirpation  of  all  parathyroid  tissues  it  can 
apparently  only  be  cured  by  a  successful  graft  of  a  parathyroid  from 
an  animal  of  the  same  species.  The  condition  has  often  been  found  to 
occur  after  complete  removal  of  the  thyro-parathyroid  apparatus  in 
man  and  may  be  sufficiently  serious  to  threaten  life,  unless  suitable 
measures  are  taken  to  combat  the  effects  of  parathyroid  loss.* 

In  order  to  prevent  the  accession  of  tetany  in  operations  for  re- 
moval of  thyroid  tumours  it  is  usually  necessary  to  leave  at  least  two 
of  the  four  parathyroids. 


*A  case  in  which  all  possible  remedies,  and  grafts  from  various  animals, 
including  a  monkey,  were  tried  without  avail,  but  which  was  rapidly  and  com- 
pletely cured  by  the  implantation  into  the  subcutaneous  tissue  of  a  parathyroid 
obtained  from  the  dead-house  is  described  by  W.  H.  Brown  in  the  Annals  of 
Surgery,  Vol.  LIII,  1911.  Others  have  furnished  similar  records. 


20  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

The  most  satisfactory  explanation  of  the  nervous  results  of  the 
removal  of  the  parathyroids  is  the  assumption  that  they  yield  to  the 
blood  a  special  autacoid — presumably  of  a  chalonic  or  restraining 
nature — which  tends  to  prevent  over-excitation  or  discharge  of  nerve- 
cells.  It  has  been  suggested  that  the  over-excitation,  since  it  occurs 
most  markedly  in  carnivora,  is  induced  by  products  of  protein  metabol- 
ism. Some  species  exhibit  no  symptoms  whatever — at  least  when  the 
operation  is  performed  on  the  adult.  Horsley  stated  that  this  is  the 
case  with  birds  and  rabbits;  but,  according  to  Gley,  the  latter  are 
affected  if  care  is  taken  to  find  and  remove  all  four  parathyroids,  and 
Doyon  and  Jouty  obtained  typical  tetany  in  hens  which  had  been 
parathyroidectomized.  Vincent  and  Jolly  found  that  rats  and  guinea- 
pigs  do  not  seem  to  suffer  from  removal  of  their  parathyroids,  but 
Christiani  and  Erdheim  both  describe  tetania  parathyreopriva  in  rats: 
and  Pfeiffer  and  Meyer  obtained  it  in  mice.  According  to  Vincent 
and  Jolly  badgers  are  totally  unaffected  by  complete  removal  of  both 
thyroids  and  parathyroids. 

It  is  possible  that  insufficient  attention  has  been  paid  to  age  by 
many  who  have  experimented  on  the  subject.  For  it  is  certain  that 
young  animals  are  much  more  susceptible  both  to  thyroidectomy  and  to 
parathyroidectomy  than  adults.  This  is  strikingly  exemplified  in  recent 
experiments  by  v.  Eiselsberg  and  by  Sutherland  Simpson  on  sheep  and 
lambs :  the  sheep  showing  no  symptoms  whatever,  while  the  lambs  ex- 
hibited both  symptoms  of  tetany  and  arrest  of  development  with  super- 
vention of  cretinism.  Adult  goats  on  the  other  hand  exhibit  well 
marked  tetania  parathyreopriva.  In  monkeys  this  condition  has  most 
generally  been  missed,  but  it  sometimes  occurs. 

Effects  on  metabolism. — An  observation  which  has  frequently  been 
made  after  parathyroidectomy  is  the  occurrence  of  changes  in  the 
growth  and  structure  of  the  bones  and  teeth.  Naturally  these  changes 
are  only  seen  if  the  animals  survive  the  operation  for  some  time.  In 
the  teeth  the  calcification — especially  of  the  dentine — appears  to  be 
delayed  (young  rats)  and  in  the  skeleton  the  bones  generally  remain 
smaller  than  in  the  controls:  the  healing  of  fractures  is  also  said  to 
be  delayed.  If  these  changes  are  the  direct  result  of  the  removal  of 
the  parathyroids  there  is  thus  some  reason  for  believing  that  these 
glands  produce  a  second  autacoid  which  is  able  to  influence  calcium 
metabolism,  and  a  further  foundation  for  this  is  met  with  in  the  fact 
that  more  than  one  observer  has  described  an  increase  of  calcium 
excretion  in  parathyroidectomized  animals.  In  connexion  with  this 
subject  but  pointing  in  the  opposite  direction  it  is  noteworthy  that  many 


THE    THYROID   APPARATUS  21 

cases  of  osteomalacia  have  been  found  to  be  associated  with  hyperplasia 
(adenoma)  of  one  or  more  parathyroids  and  therefore  presumably  with 
a  condition  of  hyperparathyroidism. 

MacCallum  and  Voegtlin  found  that  the  effects  of  parathy- 
roidectomy  could  be  removed  by  injection  of  extract  of  parathyroid. 
The  extract  has  also  been  used  with  some  success  in  man  by  Halsted. 
Extract  of  pituitary  is  said  by  Ott  to  have  a  similar  effect.  The  same 
result  was  obtained  by  MacCallum  from  the  administration  of  calcium 
salts,  both  subcutaneously  and  by  the  mouth.  According  to  Biedl, 
however,  these  salts  do  not  prolong  life  after  the  operation;  and  in  my 
experience  they  may  altogether  fail  either  to  prevent  or  alleviate  post- 
operative tetany.  According  to  Carlson  and  Jacobson,  the  action  of 
calcium  salts,  when  it  occurs,  is  like  that  of  other  substances  which 
decrease  the  excitability  of  the  nervous  system.  No  other  substance 
appears  to  exhibit  the  specific  action  on  the  nervous  system  of  the  para- 
thyroid autacoid. 

Hyper-par  afkyroidism. — According  to  Ott  extracts  of  parathyroid 
when  injected  intravenously  have  an  entirely  different  effect  from  those 
of  thyroid.  He  states  that  the  blood-pressure  is  first  raised,  then 
lowered;  that  they  increase  the  rate  of  respiration;  that  they  are 
diuretic,  acting  directly  on  the  renal  epithelium,  and  that  in  large 
doses  they  have  the  effect  of  lowering  the  body  temperature.  Also  that 
applied  locally  the  extracts  increase  the  extent  of  the  contraction  both 
of  intestines  and  uterus,  and  dilate  the  pupil. 

Clinical  evidence.  Various  clinical  symptoms  have  been  ascribed  to  patho- 
logical changes  in  the  parathyroids,  which  have  been  supposed  to  lead  (1)  in 
the  direction  of  atrophy  or  diminished  secretion  (hypo-parathyroidism)  or  (2) 
in  the  direction  of  enlargement  or  increased  activity  (hyper-parathyroidism) ,  or 
(3)  in  that  of  altered  secretion  (dys-parathyroidism) .  To  the  first  condition 
have  been  ascribed  manifestations  resembling  those  of  tetania  parathyreopriva. 
These  occur  under  various  circumstances,  e.  g.  during  pregnancy,  in  the  course 
of  infectious  diseases,  and  in  tetania  neonatorum.  In  some  of  these  cases 
degenerative  changes  or  haemorrhages  have  been  described  in  the  parathy- 
roids. But  other  cases  have  been  recorded  in  which  changes  of  a  similar 
character  have  been  found  post  mortem  in  the  parathyroids  without  symptoms 
of  tetany  having  been  noticed  during  life.  Attempts  have  also  been  made  to 
associate  conditions  showing  increase  of  response  to  reflex  or  to  cortical  stim- 
uli, e.  g.  such  as  occur  in  Thomseris  disease  or  in  paralysis  agitans,  with  a 
condition  of  chronic  deficiency  of  parathyroid  secretion.  And  on  the  other 
hand  it  has  been  suggested  that  pseudoparalytic  conditions,  such  as  those  which 
are  found  in  myotonia  paralytica  and  myasthenia  gravis,  are  due  to  chronic 
increase  of  the  secretion.  But  the  evidence  in  support  of  these  views  of  the 
origin  of  such  affections  is  by  no  means  convincing. 


22  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

The  theory  that  the  parathyroids  serve  the  purpose  of  destroying 
poisonous  products  of  metabolism  which  are  elaborated  in  the  main 
thyroid — apart  from  its  a  priori  improbability — has  received  no  support 
from  the  results  of  experiment.  If  the  removal  of  the  parathyroids 
were  to  be  explained  in  this  manner,  simple  parathyroidectomy  should 
produce  much  more  acute  symptoms  than  total  removal  of  the  whole 
thyroid  and  parathyroid  apparatus,  but  Biedl  states  that  there  is  no 
difference  in  the  acuteness  of  the  symptoms.  It  is  however  possible 
that,  as  already  stated,  the  symptoms  of  tetany  may  be  produced  by  the 
accumulation  in  the  blood  of  toxic  intermediate  products  of  protein 
metabolism,  such  as  appear  when  the  metabolic  functions  of  the  liver 
are  interfered  with.  If  this  is  so  it  might  be  inferred  that  the  para- 
thyroids produce  an  autacoid  of  hormonic  nature  which  excites  some 
other  organ  or  organs  (e.  g.  the  liver)  to  complete  the  metabolism  of 
proteins.  But  the  simplest  theory  to  explain  the  phenomenon  observed 
is  that  already  suggested,  which  assumes  the  production  of  a  chalonic 
autacoid  serving  to  diminish  the  excitability  of  nerve-cells.  This  hypo- 
thetical autacoid — which  it  must  be  well  understood  has  never  been, 
isolated — may  provisionally  be  termed  parathyrine.  We  shall  see  that 
there  is  reason  to  believe  that  the  main  thyroid  produces  an  autacoid 
with  an  opposite  tendency. 

THE   EFFECTS   OF   REMOVAL   AND   OF   ATROPHY   OF   DEGENERATION    OF 
THYROID  (Two  OR  MORE  OF  THE  PARATHYROIDS  BEING  LEFT). 

Considerable  variations  are  found  with  animals  of  different  species 
and  even  with  individuals  of  the  same  species.  As  with  parathy- 
roidectomy, thyroidectomy  produces  the  most  marked  results  in  young 
animals.  Similar  results  are  obtained  in  cases  of  spontaneous  atrophy 
of  the  gland,  or  when  such  a  change  in  structure  as  interferes  with  its 
functions  occurs  in  young  children.  There  is  arrest  of  growth,  especially 
of  the  skeleton,  the  cartilage-bones  long  remaining  incompletely  ossified ; 
development  of  the  generative  organs  is  much  delayed;  the  integument 
is  swollen,  the  surface  of  the  skin  dry;  the  hair  thin;  the  face  pale  and 
puffy;  the  abdomen  swollen;  the  nose  depressed;  the  hands  and  feet 
are  podgy.  The  fontanelles  of  the  skull  remain  open.  The  muscles  are 
limp  and  weak.  Deaf -mutism  is  common.  The  highest  functions  of  the 
nervous  system  remain  undeveloped:  this  is  due  to  an  arrested  develop- 
ment of  cells  of  the  cortex  cerebri. 

The  above  combination  of  symptoms  forms  the  condition  known  as 
cretinism.  This  may  be  either  sporadic  or  endemic;  the  former  gen- 
erally associated  with  absence  of  early  atrophy  of  the  thyroid;  the 


THE   THYROID  APPARATUS  23 

latter  with  goitrous  degeneration:  but  the  differential  diagnosis  is  not 
always  easy  as  most  of  the  symptoms  are  similar.  Of  endemic  cre- 
tinism, according  to  McCarrison,  there  are  in  the  Himalayan  valleys  two 
types,  the  myxoedematous  and  the  nervous:  the  latter  is  presumably 
associated  with  atrophy  of  parathyroids;  whilst  in  the  former  the  para- 
thyroids are  unaltered.  This  is  the  type  chiefly  met  with  in  Europe. 
These  symptoms  do  not,  however,  show  themselves  until  some  little 
while  after  birth,  in  spite  of  the  absence  of  a  thyroid.  The  absence 
appears  to  be  sufficiently  compensated  for,  for  a  time  at  any  rate,  by 
autacoids  conveyed  from  the  mother's  thyroid  to  the  child;  before  birth 
through  the  placenta,  after  birth  through  the  milk.  If  the  atrophy  is 
congenital — in  which  case  it  usually  takes  the  form  of  complete  lack  of 
development  of  the  thyroid  proper,  the  parathyroids  being  generally 
present  and  well  developed — the  condition  of  cretinsim  and  all  the 
above  symptoms  are  well  marked. 

If  either  thyroid  atrophy  is  present  or  in  the  adult  subject  such 
degenerative  changes  take  place  in  the  gland  as  materially  affect  its 
functions,  the  condition  known  as  myxoedema  (or  Myxoedema  adult orum 
to  distinguish  it  from  the  corresponding  affection  of  the  child)  becomes 
manifested.  This  condition,  which  is  much  more  common  in  females 
than  in  males,  was  described  by  Gull  in  1873,  and  recognized  by  him 
to  be  a  cretinoid  condition  of  adult  life;  while,  in  1877,  Ord,  who  gave 
to  the  affection  the  name  myxoedema — which  was  however  based  on  a 
misapprehension — showed  that  it  is  associated  with  changes  in  the 
thyroid.  It  is  characterized  by  thickening  and  swelling  of  the  integu- 
ment, which  pits  on  pressure,  the  pitting  disappearing  on  relaxing  the 
pressure :  by  the  skin  becoming  dry  and  the  hairs  falling  out :  by  a  low 
body  temperature,  and  by  mental  dullness  and  general  impairment  of 
sensibility.*  Both  in  spontaneous  and  in  operative  myxoedema  the 
metabolic  processes  are  diminished  in  activity  so  that  although  less 
food  is  taken  the  body  weight  may  increase.  Eegenerative  changes  also 
occur  more  slowly.  There  is  usually  a  considerable  deposition  of  fat, 
especially  under  the  skin.  The  activity  of  the  sexual  functions  is  dimin- 
ished in  both  sexes.  There  is  a  diminution  in  the  amount  of  oxygen 
consumed  and  in  the  amount  of  nitrogen  excreted.  There  is  increased 
tolerance  for  sugar  and  a  considerably  larger  amount  than  usual  (as 
much  as  300  g.)  may  be  taken  without  producing  glycosuria.  Never- 
theless glycosuria  occurs  sometimes,  but  is  not  excessive. 


*Brun  and  Mott  found  in  three  cases  of  myxcedema  in  the  human  subject, 
general  chromatolysis  of  nerve-cells  of  subacute  character:  they  regard  these 
changes  as  secondary  to  the  thyroid  affection. 


24  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

Symptoms  similar  to  those  of  myxoedema  are  produced  as  the  re- 
sult of  surgical  removal  of  the  thyroid  in  man.  This  was  first  apparent 
as  the  result  of  the  effects  of  operation  for  goitrous  tumours  ( J.  and  A. 
Reverdin,  Th.  Kocher).  The  Reverdins  indeed  spoke  of  the  condition 
as  one  of  post-operative  myxoedema,  whilst  Kocher  termed  it  cachexia 
strumipriva.  It  begins  to  show  itself  at  a  variable  period  after  opera- 
tion— from  a  few  days  to  months  or  even  years — and  is  more  readily 
produced  in  young  than  in  older  subjects.  It  is  sometimes  accompanied 
by  symptoms  of  tefany:  when  present,  these  symptoms  are  presumably 
referable  to  involvement  of  parathyroids.  According  to  Kocher,  the 
patients  rarely  survive  the  complete  loss  of  the  thyroid  for  more  than 
seven  years.  To  prevent  serious  ill  effects  at  least  one-fourth  of  the 
organ  must  be  left. 

The  above  symptoms,  whether  due  to  congenital  atrophy  or  to 
operative  removal,  can  be  allayed  or  entirely  removed  by  successful 
implantation  of  pieces  of  thyroid  (Schiff)  an  operation  which  has  how- 
ever rarely  succeeded  in  man*  or  by  administration  of  thyroid  sub- 
stance or  extract  either  hypodermically  (Murray)  or  by  the  mouth 
(Mackenzie  and  Fox).  Patients  suffering  from  the  effects  of  loss  of 
thyroid  secretion,  whether  this  take  the  form  of  cretinism,  myxoedema 
or  cachexia  strumipriva,  can  be  completely  restored  to  health  and  kept 
normal  for  apparently  any  length  of  time  by  buccal  administration 
of  the  gland  or  its  extracts.  If  the  treatment  be  intermitted  the 
symptoms  almost  at  once  begin  to  reappear.  The  effects  are  therefore 
obviously  due  to  the  loss  of  the  autacoid  contained  in  the  internal 
secretion.  This  autacoid  actively  influences  the  metabolic  processes  of 
the  body,  either  directly  or  indirectly  promoting  the  nutrition  of  certain 
tissues,  especially  the  connective  tissues  and  the  tissues  of  the  nervous 
system. 


EFFECTS  OF  DIMINUTION  OF  THYROID  SECRETIONS:     HYPIRTHYROIDISM. 

.  Enlargement  of  the  thyroid  such  as  occurs  in  endemic  goitre,  in 
spite  of  a  great  increase  in  volume  of  the  gland,  is  commonly  not  at- 
tended by  symptoms  of  hyperthyroidism,  but  the  reverse.  Sometimes 
such  enlargement  is  the  result  of  malignant  cell-proliferation  (carcinoma 
or  sarcoma)  ;  in  this  case  the  functions  of  the  organ  are  as  a  rule  still 


*Kocher  has,  however,  lately  published  93  cases  of  attempted  transplanta- 
tion, 23  of  which  were  cured  as  the  result  of  the  operation  and  18  showed  improve- 
ment, although  thyroid  feeding  had  to  be  continued  to  some  extent. 


THE    THYROID   APPARATUS  25 

carried  on.*  The  enlargement  of  the  gland  in  endemic  goitre  generally 
takes  the  form  of  a  diffuse  hypertrophy:  the  follicles  enlarge  and  their 
epithelium  proliferates:  new  follicles  also  become  formed.  There  is 
nearly  always  a  tendency  for  the  colloid  to  accumulate.  This  ultimately 
causes  distension  of  the  vesicles  and  flattening  of  their  epithelium, 
which  may  eventually  undergo  almost  complete  degeneration.  A  char- 
acteristic degeneration  of  the  arteries  of  the  gland  has  also  been  de- 
scribed. 

Whilst  the  above  are  the  usual  changes  found  in  endemic  goitre, 
many  exceptions  are  met  with.  One  would  expect  from  the  above 
description  that  the  enlarged  gland  was  yielding  an  excessive  amount  of 
secretion,  and  as  a  matter  of  fact,  endemic  goitre  is  occasionally  char- 
acterized in  its  early  stages  by  symptoms  suggestive  of  hypersecretion 
and  resembling  some  of  those  seen  in  incipient  exophthalmic  goitre. 
More  often  these  symptoms  of  hyperthyroidism  are  absent :  generally 
from  the  first,  and  always  eventually,  the  appearances  which  show 
themselves  are  unquestionably  symptomatic  of  hypothyroidism.  This 
must  mean  that  even  if  the  secretion  is  being  produced  in  abundance 
it  is  not  of  a  normal  character,  the  normal  autacoid  being  either  absent 
or  deficient  in  quantity.  Possibly  the  enlargement  of  the  gland  repre- 
sents an  attempt  by  nature  to  compensate  for  such  deficiency. 

EFFECTS  OF  INCREASE  OF  THYROID  SECRETIONS:    HYPERTHYROIDISM. 

The  effects  of  a  too  great  amount  of  the  thyroid  autacoids  in  the 
circulating  blood  can  be  investigated  either  by  their  introduction 
directly  into  the  circulation  or  indirectly  by  other  channels  such  as  the 
alimentary  canal;  or  by  studying  the  symptoms  of  those  affections  in 
which  there  is  reason  for  believing  that  an  excess  of  these  autacoids  is 
being  secreted  by  the  gland. 

The  immediate  results  of  intravenous  injection  are  relatively  slight. 
The  most  common  effect  is  to  produce  a  marked  but  evanescent  fall 
of  blood-pressure,  which  is  mainly  due  to  dilatation  of  the  peripheral 
vessels,  complicated  in  some  animals  (cat)  by  an  excitation  of  the 
vagus  centre  and  consequent  slowing  of  the  heart.  Whether  these  par- 
ticular effects  are  specific  is  uncertain;  at  any  rate  somewhat  similar 
results  are  obtained  from  many  other  organ  extracts.  According  to 


*  It  is  a  significant  fact  in  connexion  with  the  genesis  of  malignant  tumours 
that  when  in  such  cases  the  whole  of  the  gland  is  removed  by  the  surgeon, 
should  there  be  any  metastatic  growths  elsewhere,  e.  g.  in  the  liver,  the  usual 
symptoms  of  cachexia  thyreopriva  do  not  show  themselves  (v.  Eiselsberg). 


26  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

Lohmann  and  others  the  depressor  substance  in  thyroid  extract  is 
cholin.  Asher  states  that  the  fall  of  blood-pressure  and  effects  on  the 
heart  are  not  seen  in  the  rabbit,  but  other  results  are  produced,  for  im- 
mediately after  such  injection  in  that  animal  the  excitability  of  the 
vagus  and  of  the  depressor  nerve  is  increased,  and  the  changes  in 
blood-pressure,  pupil,  etc.,  produced  by  a  particular  dose  of  adrenine 
are  enhanced.  Given  by  the  mouth  in  the  human  subject  thyroid  ex- 
tract produces  lowering  of  the  blood-pressure.*  Large  doses  are  fol- 
lowed by  tachycardia  (rapid  pulse),  often  with  some  irregularity; 
nervous  excitability;  flushing  of  the  skin,  with  feeling  of  heat;  increase 
of  perspiration;  and  increase  of  nitrogen  metabolism.  If  long  cor- 
tinued  the  fat  of  the  body  is  diminished  and  glycosuria  may  be  caused. 
Alimentary  glycosuria  is  also  more  easily  produced  than  normally. 
In  extreme  cases  there  may  be  exophthalmos  and  other  effects  referable 
to  cervical  sympathetic  excitation,  such  as  dilatation  of  the  pupil  and 
(in  animals)  retraction  of  the  third  eyelid;  psychical  excitement;  sleep- 
lessness; tremors  of  the  limbs;  in  short,  most  of  the  symptoms  of  ex- 
ophthalmic goitre.  The  addition  to  the  food  of  animals  of  even  a  small 
amount  of  thyroid  gland  has  the  effect  of  increasing  nitrogenous 
metabolism,  as  shown  by  the  increase  of  nitrogen  in  the  urine.  This 
is  accompanied  by  a  corresponding  increase  in  food  consumption.  Some 
of  the  additional  nitrogen  thus  ingested  is  retained  in  the  body  but  this 
is  compensated  for  by  increased  fat  consumption,  so  that  the  difference 
in  growth  curve  of  the  thyroid-fed  animals  and  the  controls  is  but 
slight.  With  large  doses  of  thyroid  there  soon  ensues  marked  loss  of 
weight  due  to  increased  nitrogenous  excretion  and  loss  of  fat. 

The  colloid  contents  of  the  thyroid  vesicles  are  greatly  increased 
during  the  ingestion  of  much  thyroid  substance. 

Exophthalmic  goitre. — This  affection,  first  described  by  Parry  (1825) 
and  associated  by  him  with  the  thyroid,  is  also  associated  with  the 
names  of  Graves  (1835)  and  Basedow  (1840),  both  of  whom  called 
special  attention  to  the  symptoms.  The  name  exophthalmic  goitre  ex- 
presses its  most  prominent  sign.  The  disease  is  associated  with  enlarge- 
ment of  the  thyroid.  According  to  Moebius  and  Greenfield  the  en- 
largement is  accompanied  by  hypersecretion  which  is  the  direct  cause 
of  the  symptoms,  this  opinion  being  founded  on  the  fact  that  (1)  as  has 
just  been  mentioned,  some  of  the  symptoms  of  the  disease  can  be  pro- 
duced by  excessive  administration  of  thyroid,  and  (2)  that  the  symp- 


*In  diabetic  subjects  it  is  said  to  cause  the  opposite  result — an  effect  lasting 
for  several  days. 


THE   THYROID   APPARATUS  27 

tonis  are  for  the  most  part  opposite  in  character  to  those  which  are 
known  to  be  produced  by  atrophy  or  diminution  of  function  of  the 
gland.  Thus  there  is  a  rapid  and  often  irregular  pulse;  nervous  and 
psychical  excitation,  with  muscular  tremors;  a  feeling  of  warmth  in 
the  skin,  and  throbbing  of  cutaneous  vessels,  often  accompanied  by  pro- 
fuse sweating;  shallow  respiration;  markedly  increased  metabolism 
(especially  nitrogenous)  with  abnormal  appetite  and  loss  of  body  fat; 
a  decreased  assimilatory  power  for  carbohydrates;  an  anxious  restless 
expression;  prominence  of  the  eyeballs;*  wide  palpebral  aperture,  often 
with  dilatation  of  pupils.  The  enlargement  of  the  thyroid  may  involve 
only  one  lobe.  The  enlarged  gland  pulsates,  and  gives  a  murmur  on 
auscultation. 

Exophthalmic  goitre  is  far  more  common  in  the  female  than  in  the 
male  (as  4.6  to  1),  a  fact  which  may  be  related  to  the  enlargement  of 
the  gland,  which  usually  occurs  in  the  female  at  puberty  and  during 
pregnancy.  It  is  generally  associated  with  a  persistent  thymus,  an 
internal  secretion  from  which  has  by  some  authors  been  credited  with 
the  production  of  certain  of  the  symptoms  of  the  disease.  About 
13.5%  have  polyuria  without  sugar.  Only  2%  have  glycosuria,  although 
alimentary  glycosuria  is  not  uncommon.  Albuminuria  is  present  in 
about  11%. 

The  histological  appearances  are  conformable  with  the  theory  of  a 
hypersecretion  (which  may  however  be  abnormal).  The  gland  is 
greatly  enlarged,  and  the  individual  vesicles  are  larger  than  usual  and 
tend  to  run  together.  The  interstitial  tissue  is  increased  in  amount 
and  assumes  a  lymphoid  appearance,  often  with  characteristic  germinal 
centres.  The  follicle  wall  tends  to  grow  into  the  interior  of  the  en- 
larged and  conjoined  follicles  in  the  form  of  ridges  and  papillae,  thus 
increasing  the  surface  for  secretion  and  giving  the  cavities  an  irregular 
aspect.  On  the  other  hand,  some  follicles  undergo  retrograde  changes, 
and  may  even  disappear.  The  cells  lining  the  follicles  acquire  a 
columnar  form:  in  later  stages  they  may  undergo  degeneration  and 
become  set  free  within  the  follicles.  The  contents  of  the  follicles  are 
more  fluid  than  in  the  normal  thyroid  and  stain  less. 

Direct  proof  of  hypersecretion  is  thought  to  be  furnished  by  the 
experiments  of  Reid  Hunt,  who  found  that  the  blood  of  a  person 
afflicted  with  exophthalmic  goitre  increases  the  resistance  of  mice  to 


*It  is  stated  that  the  exophthalmos  may  be  unilateral,  in  which  case  it  can 
hardly  be  produced  entirely  by  the  circulation  of  an  autacoid  in  the  blood  with- 
out the  intervention  of  a  nervous  factor. 


28  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

the  poisonous  effects  of  acetonitrile ;  a  reaction  he  had  previously 
found  to  take  place  after  injection  of  thyroid  extract.  Asher  and 
Flack  have  also  obtained  physiological  evidence  of  the  existence  of 
excess  of  thyroid  secretion  in  the  blood  in  this  disease.  Others,  on  the 
contrary,  have  found  that  injection  into  animals  of  serum  from  a 
patient  in  whom  the  disease  is  active  does  not  produce  the  same  effects 
as  thyroid  juice;  and  although  in  dogs  small  doses  of  extract  from 
an  exophthalmic  goitre  cause  increased  rate  of  heart-beat  and  some 
rise  of  blood-pressure,  this  is  soon  followed  by  the  opposite  condition. 
Moreover  the  action  of  the  sympathetic  is  sometimes  lessened  and  that 
of  the  vagus  may  be  reversed.  The  symptoms  are  therefore  produced, 
according  to  Gley  and  Sahli,  not  by  excess  of  normal  thyroid  secretion 
circulating  in  the  blood,  but  probably  as  the  result  of  the  production 
of  a  perverted  secretion  (dysthyroidism). 

THE  NATURE  AND  MODE  OF  ACTION  OF  THE  AUTACOID  SUBSTANCE  CON- 
TAINED IN  THE  INTERNAL  SECRETION  OF  THE  THYROID. 

The  active  principle  of  the  thyroid  has  been  usually  assumed  to  be 
represented  by  the  non-proteid  nitrogenous  material  known  as  iodo- 
thyrin  or  the  compound  proteid  iodo-thyro-globulin.  The  former  was 
prepared  from  thyroid  by  Baumann  (1895)  and  found  by  him  to  con- 
tain a  marked  amount  of  iodine  (.3  to  .9  per  mille  of  dry  substance). 
In  confirmation  of  this  view  the  experiments  of  Reid  Hunt  and  others 
seemed  to  show  that  the  production  of  the  autacoid  is  promoted  by  ad- 
ministration of  iodides  and  that  there  is  a  certain  relation  between  the 
physiological  activity  of  the  gland  and  its  iodine  content.  But  the 
fact  that  even  when  the  dessicated  thyroid  contains  a  considerable 
amount  of  iodine  it  is  sometimes  found  to  have  no  action  suggests  that 
Baumann 's  substance  is  not  the  actual  autacoid,  although  it  may  be 
associated  with  it.  We  are  in  fact  still  in  the  dark  so  far  as  the  true 
nature  of  this  autacoid  is  concerned  and  it  seems  better  to  express  our 
ignorance  by  a  term  which  implies  no  theory,  leaving  the  question  of 
its  identity  with  iodo-thyrin  or  iodo-thyro-globulin  open.  I  propose 
therefore  provisionally  to  apply  the  word  thyrine  to  denote  the  active 
principle,  whether  it  be  identical  with  or  contained  in  the  iodo-thyrin 
of  Baumann  or  not. 

As  we  have  already  seen,  the  autacoid  of  the  parathyroid  (para- 
thyrine)  is  probably  of  chalonic,  i.  e.  of  inhibitory  nature,  serving 
to  keep  in  check  the  activity  of  nerve-cells.  On  the  other  hand,  the 
autacoid  of  the  thyroid  (thyrine)  acts  like  a  hormone  in  increasing 


THE   THYROID   APPARATUS  29 

the  excitability  of  nerve-cells.  This  increase  of  excitability  is  espe- 
cially well  marked  in  connexion  with  the  sympathetic.  Here  the  ques- 
tion arises:  Is  this  a  direct  effect  on  the  sympathetic  system  or  is  it  in- 
direct through  the  adrenals  ?  which  are  stimulated  to  increased  secretory 
activity  by  excess  of  thyroid  in  the  blood.  The  answer  is  not  easy. 
But  it  may  be  stated  that  although  certain  symptoms  of  hyperthy- 
roidism  are  similar  to  those  produced  by  excess  of  adrenine  in  the  blood, 
others  are  not  so.  This  is  the  case  with  the  flushing  of  the  skin,  which 
is  due  to  vascular  dilatation;  whereas  adrenine  ordinarily  produces 
vasoconstriction.  Further,  excess  of  adrenine  in  the  blood  leads  to 
glycosuria,  which  is  not  as  a  rule  seen  in  exophthalmic  goitre.  More- 
over it  is  undoubtedly  the  case  that  the  administration  of  adrenine 
exercises  a  markedly  beneficial  effect  in  some  cases  of  exophthalmic 
goitre:  a  fact  which  would  be  inexplicable  on  the  theory  that  the 
results  of  hyperthyroidism  are  simply  due  to  excitation  of  the  supra- 
renals  and  the  production  of  an  excess  of  adrenine. 

But  although  many  of  the  effects  of  thyroid  feeding  and  of  hyper- 
thyroidism otherwise  produced  can  be  explained  by  the  presence  of 
excitatory  or  hormonic  autacoids,  it  is  not  possible  to  explain  the  results 
produced  by  thyroid  deprivation,  or  hypothyroidism,  upon  the  body 
generally  and  certain  organs  in  particular  merely  by  assuming  the 
absence  of  these  excitatory  substances.  For  loss  of  the  thyroid  is 
followed  by  increased  growth  and  presumably  activity  in  certain  organs. 
This  is  notably  the  case  with  the  pituitary;  and  although  it  has  been 
suggested  that  this  a  case  of  vicarious  increase  of  size  associated  with 
the  performance  of  similar  functions,  the  similarity  of  the  functions 
of  the  two  glands  is  far  from  obvious.  A  more  probable  explanation  is 
that  besides  a  hormone  which  excites  nerve-cells,  the  thyroid  secretes  an 
autacoid  of  chalonic  nature  which  restrains  the  activity  of  certain  other 
organs,  such  as  the  pituitary:  on  removal  of  the  thyroid  this  restraint 
is  abolished,  and  over-activity  is  the  result. 

The  thyroid  autacoids  also  affect  the  growth  of  the  thymus  gland, 
which  has  been  found  to  undergo  an  increase  in  size  in  foetal  animals 
after  thyroid  feeding  of  the  pregnant  mother  (guineapigs)  :  on  the 
other  hand  the  suprarenal  capsules  and  the  thyroid  itself  have  been 
found  to  undergo  a  diminution  in  weight  under  these  circumstances. 
Hoskins,  who  furnishes  this  observation,  ascribes  the  effect  upon  the 
growth  of  the  thymus  to  stimulation  by  a  hormone  furnished  by  the 
thyroid:  if  this  is  so,  the  opposite  results  on  suprarenal  and  thyroid 
should  be  ascribed  to  an  autacoid  of  opposite  sign.  In  conformity 
with  this  idea  the  diminished  growth  of  the  skeleton  and  of  the  gen- 


30  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

erative  organs  which  follow  thyroid  removal  in  young  animals  should 
be  put  down  to  the  absence  of  a  hormone,  which  promotes  their  develop- 
ment. 

A  close  relationship  exists  between  the  size  and  structure  of  the 
thyroid  and  the  state  of  general  nutrition  of  the  animal.  The  effect  of 
variations  of  diet  upon  the  thyroid  has  been  studied  in  rats  by  Chal- 
mers Watson,  who  has  shown  that  all  transitions  from  an  active  or 
superactive  organ  with  highly  developed  columnar  epithelium  and  ir- 
regular large  vesicles  and  without  any  great  accumulation  of  colloid, 
to  a  gland  with  flattened  epithelium  and  large  spheroidal  vesicles 
distended  by  deeply  staining  "colloid"  are  exhibited  under  the  in- 
fluence of  different  nutritive  substances  in  the  diet:  the  former 
conditions  being,  in  the  rat,  typically  seen  when  the  animals  have  been 
fed  upon  a  mixed  food  such  as  bread  and  milk:  the  latter  when  the 
diet  has  been  composed  of  lean  meat.  Prolonged  feeding  of  rats  with 
lean  meat  led  eventually  to  a  shrinking  in  size  of  tfce  vesicles  and  of 
the  whole  organ,  these  changes  being  associated  with  dry  ness  of  skin, 
falling  off  of  hair,  and  other  evidences  of  ill  health;  but  in  carnivora 
results  of  this  kind  were  not  observed. 

INTERACTION  OF  THE  THYROID  WITH  OTHER  ORGANS. 

The  generative  organs. — Th,e  important  influence  exerted  by  the 
thyroid  secretion  on  nutrition  generally  is  no  doubt  responsible  for  the 
fact  that  hardly  any  organ  in  the  body  remains  unaffected  as  a  result 
of  its  complete  removal  or  atrophy.  But  the  secreting  organs  with 
which  it  may  be  regarded  as  being  more  specifically  associated  are  few. 
Among  them  are  the  generative  glands.  In  the  female  the  thyroid 
becomes  enlarged  at  puberty,  during  the  menses,  and  during  preg- 
nancy. In  the  young  thyroidectomized  subject  the  generative  glands 
are  only  slowly  or  imperfectly  developed,  the  resulting  condition  being 
characteristically  one  of  sexual  infantilism.  In  the  adult  animal  (dog) 
Alquier  and  Theuveny  found  diminished  activity  so  far  as  production 
of  spermatozoa  is  concerned,  but  less  distinct  evidence  of  change  in 
the  ovary;  although  the  animals  appeared  to  come  on  less  completely 
in  heat  and  to  conceive  with  difficulty. 

The  liver  and  pancreas. — Other  effects,  of  a  more  or  less  specific 
character,  are  produced  upon  liver-glycogen.  Krause  and  Cramer  find 
that  in  the  cat  and  rat,  fed  with  thyroid,  glycogen  disappears  from 
the  liver;  but  there  is  no  glycosuria,  the  sugar  having  been  conveyed  to 
the  tissues  and  oxydised.  Parhon  has  obtained  a  similar  result  with 


THE   THYROID   APPARATUS  31 

the  rabbit.  The  thyroid  therefore  produces  mobilisation  of  .carbo- 
hydrates. Thyroid  feeding  also  tends,  as  we  have  seen,  to  dimin- 
ish the  limit  for  the  assimilation  of  sugar — this  may  be  due  to 
an  increase  in  the  secretion  of  adrenine,  or  perhaps  to  a  direct  in- 
hibitory effect  on  the  internal  secretion  of  the  pancreas. 

After  thyroidectomy  the  assimilation  limit  for  sugar  is  markedly 
raised:  and  according  to  Eppinger,  Falta  and  Kiidinger,  adrenine-gly- 
cosuria  is  greatly  diminished  or  fails  to  show  itself.  This  statement 
has,  however,  been  denied  by  Underhill  and  Hilditch.  If  the  para- 
thyroids be  included  in  the  removal  the  assimilation  limit  for  sugar  is 
lowered  and  adrenine  produces  a  stronger  glycosuria  than  in  the  normal 
animal.  The  influence  of  the  thyroids  and  parathyroids  is  therefore 
antagonistic  in  this  as  in  some  other  respects.  According  to  Lorand, 
if  a  dog  deprived  of  pancreas  and  exhibiting  glycosuria  be  thy- 
roidectomized  the  sugar  disappears  from  the  urine.  Lorand  further 
states  that  extirpation  of  the  pancreas  has  the  effect  of  increasing 
the  amount  of  colloid  in  the  thyroid  vesicles  and  that  thyroidectomy 
causes  a  marked  increase  in  the  amount  of  islet  tissue  in  the  pancreas. 
But  both  these  statements  are  difficult  to  accept  on  account  of  the  dif- 
ferences which  are  normally  present,  both  in  amount  of  colloid  in  the 
thyroid  and  in  number  of  islets  in  the  pancreas.  If  substantiated  they 
would  show  a  direct  correlation  between  the  thyroid  and  the  pan- 
creas, the  internal  secretion  of  the  thyroid  being  restrained  by  that  of 
the  pancreas  and  the  internal  secretion  of  the  pancreas  by  that  of  the 
thyroid,  so  that  when  either  gland  is  extirpated,  the  internal  secretion 
of  the  other  either  becomes  more  active  or  is  increased  in  amount. 

The  adrenals. — There  is,  however,  an  indirect  way  in  which  the 
internal  secretion  of  the  pancreas  can  be  influenced  by  thyroid  secretion, 
and  that  is  by  the  effect  which  the  secretion  produces  upon  the  activity 
of  the  secretion  of  the  suprarenal  capsules.  This  effect  is,  as  Asher 
and  Flack  have  shown,  in  the  direction  of  increase  of  excitability  of 
those  tissues,  which  are  amenable  to  the  action  of  adrenine.  And  when 
the  thyroid  is  extirpated  the  activity  of  the  secretion  of  the  suprarenals 
is  diminished.  Not  only  is  this  the  case  with  the  effects  of  adrenine,  but 
the  phenomena  generally  which  are  normally  produced  by  sympathetic 
stimulation  are  similarly  affected.  Further,  with  hyperthyrosis  such  as 
occurs  in  intense  thyroid  feeding  and  exophthalmic  goitre  most  but 
not  all  of  the  symptoms  are,  as  we  have  seen,  those  of  over-excitation 
of  the  sympathetic  and  are  similar  to  those  caused  by  adrenine.  More- 
over, there  is  some  evidence  that  the  amount  of  adrenine  in  the  blood 
is  increased  in  hyper  thy  roidism  as  well  as  that  its  activity  is  enhanced. 


32  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

Ott  and  Scott  got  increase  of  adrenine  in  the  blood  after  intravenous 
injection  of  thyroid  extract.  They  obtained,  however,  a  similar  result 
after  injection  of  other  organ  extracts.  Kraus  and  his  fellow  workers 
observed  dilatation  of  the  pupil  of  the  excised  frog's  eye  when  placed 
in  blood-serum  or  blood-plasma  of  patients  affected  by  exophthalmic 
goitre,  although  blood-plasma  of  normal  individuals  does  not  give  this 
reaction.  But  the  fact  that  some  cases  of  exophthalmic  goitre  benefit 
by  the  exhibition  of  adrenine  is  difficult  of  explanation,  since  from 
what  has  been  stated  this  should  cause  an  exacerbation  of  the  symp- 
toms. Moreover,  it  must  be  borne  in  mind  that  some  of  the  physiological 
tests  which  have  been  used  for  adrenine  would  also  be  given  by 
pituitrine,  and  this  may  be  a  factor  in  the  discussion  of  the  question. 
Kraus  has  also  obtained  chemical  evidence  of  the  presence  of  excess  of 
adrenine  in  blood  after  injection  into  animals  of  the  juice  of  thyroid 
gland  from  cases  of  exophthalmic  goitre,  and  in  such  cases  its  presence 
has  also  been  demonstrated  by  physiological  tests  (Fraenkel  with  the 
uterus;  Trendelenburg  and  Broking,  with  the  frog's  bloodvessels). 
It  may  therefore  be  assumed  that  the  secretion  of  the  thyroid  in 
exophthalmic  goitre  acts  as  a  direct  stimulant  to  the  suprarenal  cap- 
sules, causing  them  to  yield  adrenine  to  the  blood  in  larger  quantity. 

The  pituitary  body. — As  has  been  pointed  out  above,  a  very  strik- 
ing effect  is  caused  by  removal  or  atrophy  of  the  thyroid  upon  the 
pituitary  body:  which  not  only  undergoes  general  enlargement  but 
also  exhibits  well  marked  indications  of  increased  secretion.  These 
changes  will  be  described  when  the  pituitary  is  dealt  with. 

The  thymus  gland. — Reference  has  already  been  made  to  the 
anatomical  and  developmental  relationship  between  thymus  and  thy- 
roid, to  the  effect  of  thyroid  feeding  of  a  pregnant  animal  upon  the 
growth  of  the  thymus  of  the  foetus,  and  to  the  supposed  effect  of  the 
thymus  in  assisting  to  produce  the  symptoms  of  exophthalmic  goitre: 
indeed  its  removal  by  operation  has  been  recommended  and  even 
practised  in  that  affection.  In  view  of  these  circumstances  some  believe 
that  there  exists  a  mutual  relationship  between  the  two  organs,  and 
that  they  exercise — by  their  internal  secretions — some  sort  of  excitatory 
influence  upon  one  another.  In  conformity  with  this  it  has  been 
pointed  out  that  the  increase  or  diminution  in  size  of  the  two  organs 
usually  go  hand  in  hand.  But  this  can  only  be  early  in  life,  for  under 
normal  conditions  of  growth  and  development  the  thymus  is  under- 
going retrogression  whilst  the  thyroid  is  becoming  more  active  in  its 
functions.  Moreover,  the  variations  in  the  thymus  are  so  considerable, 


THE   THYROID   APPARATUS  33 

and  at  present  in  spite  of  many  observations  so  little  is  accurately 
known  regarding  the  conditions  under  which  they  occur  that  it  will 
be  wise  to  reserve  judgment  as  to  the  mutual  relations  of  this  organ 
and  the  thyroid. 

INFLUENCE  OP  THE  NERVOUS  SYSTEM  ON  THYROID  SECRETION. 

It  was  shown  by  Cyon  that  vasodilator  nerve  fibres  pass  from  the 
recurrent  laryngeal  nerves  to  the  thyroid  gland.  Ossokin  finds  the 
gland  to  be  supplied  by  both  laryngeal  nerves  and  also  by  the 
pharyngeal  branches  of  the  vagus.  Vasoconstrictors  pass  to  it  by  way 
of  the  sympathetic.  H.  Wiener  found  extirpation  of  the  inferior 
cervical  ganglion  to  be  followed  by  atrophy  of  the  gland  and  diminu- 
tion of  thyro-globulin  in  the  thyroid  of  the  same  side.  It  has  further 
been  shown  by  Asher  and  his  fellow  workers  that  the  internal  secretion 
of  the  thyroid  is  directly  influenced  by  the  nerve  fibres  which  pass  to  the 
gland  by  the  superior  and  inferior  laryngeal  nerves.  In  order  to  test 
the  amount  of  its  autacoid  in  the  blood  they  took  advantage  of  the 
fact  that  injection  of  thyroid  juice  or  extract  into  the  circulating  blood 
(1)  increases  the  excitability  of  the  vasoinhibitory  fibres  of  the  de- 
pressor nerve — or  at  least  increases  the  effect  produced  by  their  ex- 
citation; (2)  increases  the  effect  of  stimulating  the  splanchnics;  (3) 
increases  the  effect  of  stimulating  the  cardiac  vagus;  (4)  increases 
the  effect  produced  by  injection  of  a  given  dose  of  adrenine.  They 
obtained  these  results  during  stimulation  of  the  peripheral  cut  ends  of 
the  laryngeal  nerves,  but  failed  to  get  them  if  they  had  previously 
extirpated  the  thyroid.  It  has  also  been  stated  that  the  iodine  content 
of  a  thyroid  lobe  is  diminished  as  the  result  of  excitation  of  the  vagus 
of  the  same  side. 

These  observations  indicate  that  in  the  secretion  and  outpouring 
of  its  active  principles  the  thyroid  is,  like  externally  secreting  glands, 
under  the  direct  influence  of  nerves.  This  fact  serves  to  corroborate 
the  conclusion  arrived  at  from  other  considerations,  that  in  this  gland 
as  in  the  parathyroids  we  have  to  deal  with  an  organ  of  internal  secre- 
tion. The  view  which  was  at  one  time  held  that  its  function  is  merely 
that  of  a  destroyer  of  toxic  substances  circulating  in  the  blood  is  no 
longer  tenable.  The  same  may  be  said  for  an  old  idea — renovated  by 
Cyon — that  the  gland  serves  as  a  kind  of  shunt  to  regulate  the  flow 
of  blood  in  the  cranial  cavity.  This,  indeed,  has  nothing  to  support 
it  beyond  the  extreme  vascularity  of  the  gland  and  its  position  in  close 
connexion  with  the  carotids. 


34  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

LECTURE   III. 
THE  FUNCTIONS  OF   THE  ADRENAL  APPARATUS. 

The  suprarenal  capsules  or  adrenals  have  received  special  attention, 
both  from  clinicians  and  physiologists,  since  Addison  (1855)  described 
the  symptoms  of  the  disease  which  bears  his  name  and  which  he  asso- 
ciated with  degeneration  of  these  organs.  Addison 's  disease  is  char- 
acterized by  great  languor  and  general  debility,  with  weakness  and 
diminution  of  tone,  not  only  of  the  skeletal  but  of  the  vascular  and 
visceral  musculature,  feeble  action  of  heart,  loss  of  appetite,  dis- 
turbance of  the  digestive  tract,  severe  abdominal  pain  and  extreme 
emaciation.  Anaemia,  which  is  an  occasional  accompanyment  of  the 
disease,  was  regarded  by  Addison,  when  it  occurs,  as  symptomatic;  but 
it  is  probably  the  result  not  of  the  destruction  of  the  capsules  but  of 
the  intercurrent  affection  (generally  tuberculosis),  which  has  pro- 
duced their  destruction.  The  most  striking  characteristic  of  the 
disease  as  described  by  Addison  was  undoubtedly  the  pigmentation 
(bronzing)  of  the  skin,  which  occurs  as  a  diffuse  colouration  upon  the 
face  and  hands  and  other  exposed  parts  and  is  increased  in  regions 
where  there  is  some  pigmentation  normally  present,  such  as  the  areolae 
of  the  nipples  and  the  external  genital  organ.  It  is  also  found  on  the 
mucous  membrane  of  the  mouth  and  on  that  of  the  conjunctiva.  Some- 
times the  bronzing  does  not  occur;  these  cases  are  usually  the  more 
acute.  The  disease  is  fatal.  Its  course  may  be  prolonged,  "even  to  six 
or  ten  years.  In  rare  instances  recovery  has  taken  place,  and  periods 
of  improvement  lasting  many  months  may  occur "  (Osier).  Some  cases 
are  markedly  benefited  by  administration  of  suprarenal  extract  per  os 
or  hypodermically ;  others  not  at  all. 

The  cause  of  the  excessive  formation  of  pigment  is  not  understood,  but  it 
has  been  suggested  (by  Adami  and  others)  that  adrenine  may  be  derived  from 
the  same  source  as  the  melanin  of  the  skin  and  that  if  the  formation  of 
adrenine  is  interfered  with  an  excess  of  melanin  is  formed  and  deposited. 
Meirowsky  states  that  in  portions  of  skin  removed  from  patients  who  have  died 
of  Addison's  disease  an  increase  of  pigment  occurs  as  long  as  five  days  after 
death  if  the  pieces  are  kept  in  a  warm,  moist  chamber,  but  that  this  does  not 
occur  in  the  skin  from  those  who  have  died  from  other  causes.  He  suggests 
that  a  colorless  precursor  of  the  melanin  is  present  in  the  skin,  and  supposes 
this  to  become  transformed  under  the  influence  of  light.  Somewhat  similar 
observations  have  been  made  by  Konigstein  and  by  Biedl  and  Hofstatter,  on 
the  skin  of  dogs  deprived  of  their  suprarenal  apparatus:  but  negative  results 
were  obtained  with  rabbits  and  other  rodents.  In  epinephrectomized  animals 
pigmentation  of  the  skin  is  not  seen:  it  therefore  probably  requires  a  gradual 
destruction  such  as  occurs  in  chronic  disease  of  the  capsules  in  man,  a  condition 


THE  ADRENAL   APPARATUS  35 

which  has  not  hitherto  been  successfully  imitated  in  animals.  Some  observers 
have,  however,  described  pigmentation  of  the  skin  and  mucous  membranes  in 
animals  as  the  result  of  removal  of  the  adrenals,  or  as  the  result  of  removal  of 
one  and  injury  of  the  other.  But  the  evidence  of  the  production  of  pigmenta- 
tion by  the  operation  is  inconclusive. 

Structure  of  the  suprarenal  capsules. — It  is  well  known  that  the 
adrenals  consist  of  two  parts,  which  although  anatomically  united  in 
many  animals,  are  morphologically  distinct  and  are  developed  from 
different  embryonic  formations;  the  first,  known  as  the  cortex,  being- 
formed  from  mesoderm-cells  of  the  genital  ridge,  whilst  the  second  or 
medulla  is  developed  from  cells  which  belong  to  the  same  neuroblast- 
masses  as  give  rise  to  the  nerve-cells  of  the  sympathetic  ganglia.  In 
fishes  for  the  most  part  these  parts  remain  separate,  forming  the  so- 
called  inter-renal  ~body  or  bodies,  representing  the  cortex  of  the  mammal, 
and  the  paired  chromaffine  bodies,  representing  the  medulla,  But  in  all 
higher  vertebrates  the  two  parts  are  united  into  one  organ  which  is 
generally  closely  attached  to  the  kidney  on  each  side.  In  birds  and 
reptiles  the  renal  and  adrenal  tissues  interlock;  it  is  only  in  mammals 
that  the  same  condition  is  found  as  in  man,  viz.,  a  central  medulla 
with  an  enclosed  cortex. 

Accessory  suprarenals  are  not  infrequent.  They  consist  either  of  cortical 
substance  alone,  or  of  medullary  substance  alone,  or  of  the  two  combined.  They 
occur  most  commonly  between  the  kidneys  and  along  the  lower  pa  t  of  the 
abdominal  aorta  as  far  as  its  bifurcation.  In  the  male  rat  such  an  accessory 
gland  is  almost  constantly  seen  close  to  the  epididymis.  They  are  relatively 
longer  and  more  frequent  in  the  new-born  animal  than  in  the  adult,  in  which 
they  may  be  missed  altogether.  The  possibility  of  their  presence  must,  how- 
ever, be  borne  in  mind  when  considering  the  results  of  the  extirpation  or  the 
adrenals  in  animals. 

SHIELDING  OP  THE  CORTICAL  OR  INTERRENAL  PART  OF  THE  ADRENAL. 

The  cortex  of  the  adrenal  is  composed  of  epithelium-like  polygonal 
cells  arranged  mainly  in  columns  (zona  fasciculata) ,  but  near  the 
medulla  as  a  network  of  trabeculae  (zona  recticularis) .  Towards  the 
surface  the  cell  columns  end  in  rounded  and  sometimes  hollowed  out 
terminations  forming  the  so-called  zona  glomerulosa,  the  cells  of  which 
sometimes  have  a  columnar  form.  The  cells  are  usually  rather  larger 
in  the  zona  fasciculata  than  in  the  other  parts.  Characteristic  of  the 
cortical  cells  is  the  presence  of  lipoid  granules,  which  may  give  a 
yellowish  colour  to  this  part  of  the  capsule.  The  zona  recticularis  con- 
tains also  pigment  granules  which  in  some  animals  give  it  a  distinct 
brownish  colour.  The  human  foetus  is  well  known  to  have  unusually 


36  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

large  suprarenal  capsules.  It  has  been  shown  by  Elliott  and  Armour 
that  the  increased  size  is  almost  entirely  due  to  a  great  development 
of  a  innermost  part  of  the  cortex  lying  at  the  boundary  with  the 
medulla  (boundary  zone  of  cortex).* 

Its  cells  differ  from  those  of  the  rest  of  the  cortex  in  having  no  lipoid 
granules.  After  birth  they  undergo  a  fatty  change  and  the  layer  gradu- 
ally disappears,  so  that  it  is  no  longer  distinguishable  after  the  first  year. 
At  birth  what  will  be  the  cortex  of  the  adult  gland  consists  only  of  a  thin 
peripheral  layer  of  cells  containing  lipoids ;  these  cells  multiply  and  the 
layer  enlarges  pari  passu  with  the  disappearance  of  the  boundary  zone. 
A  remarkable  fact  pointed  out  by  Elliott  and  Armour  is  that  in  the 
anencephalous  foetus  the  boundary  zone  is  absent  and  the  suprarenal  re- 
sembles that  of  other  foetal  mammals. 

FUNCTIONS  OF  THE  CORTICAL  PART. 

Little  is  known  regarding  the  functions  of  the  cortex.  Its  anatomical 
relation  in  mammals  to  the  chromaffine  part  and  the  fact  that  its  blood 
passes  directly  into  the  medulla  suggests  that  its  cells  may  be  concerned 
in  the  production  of  materials  which  are  utilized  by  the  medulla)  but  as 
has  been  above  mentioned,  this  relation  fails  in  many  vertebrates.  It 
has  been  stated  by  Abelous  and  others  that  the  cortex  contains  a  pre- 
cursor of  the  adrenine  of  the  medulla  and  that  if  left  standing  for  twenty- 
four  hours  in  an  incubator  a  considerable  amount  of  a  substance  giving 
the  reactions  of  adrenine  accumulates  within  it.  But  according  to  the 
investigations  of  Bayer  the  results  obtained  are  not  ascribable  to  adrenine, 
but  to  the  products  of  protein  decomposition.  The  statement  that  the 
cortex  becomes  enlarged  during  pregnancy  and  is  small  in  cases  of  de- 
ficient sexual  development  seems  to  give  evidence  of  some  relationship 
\between  it  and  the  generative  glands ;  but  whether  this  is  direct,  or  oper- 
ates through  other  ductless  glands — such  as  the  thyroid  and  pituitary— 
is  not  known.  The  close  connection  between  the  development  of  the  sex- 
ual organs  and  that  of  the  suprarenal  cortex  has  been  especially  insisted 
upon  by  Glynn. 

It  has  also  been  suggested  that  a  function  of  the  cortex  may  be  to 
neutralize  deleterious  products  which  are  formed  in  the  process  of  metab- 
olism of  other  organs  or  are  introduced  from  outside.  But  this  suppo- 
sition has  received  no  support  as  the  result  of  experiments. 


*Not  to  be  confounded  with  the  "intermediate  zone"  of  Virchow,  which  is 
a  very  thin  layer,  pigmented  in  old  age,  lying  at  the  junction  of  the  cortex  and 
medulla. 


THE   ADRENAL   APPARATUS  37 

One  of  the  most  striking  facts  connected  with  the  cells  of  the  cortex 
is  their  richness  in  lipoids  and  fats,  which  have  been  chemically  investi- 
gated by  many  workers.  Biedl  (Innere  Sekretion,  Vol.  II,  p.  60,  of  2d 
Edition)  gives  the  following  figures  from  his  own  investigations.  The 
suprarenals  of  the  pig  yielded  74.61  per  cent  of  water  and  25.39  per  cent 
of  dry  residue.  Of  the  latter,  61.12  per  cent  consisted  of  proteins,  etc., 
and  38.88  per  cent  of  lipoid — besides  some  insufficiently  distinguishable 
extractices.  In  this  analysis  the  medulla  was  included,  and  as  this  is  poor 
in  lipoids  the  lipoid  contents  of  the  cortex  must  have  a  much  higher  value : 
far  higher  than  any  other  non-nervous  tissue. 

Their  microscopic  appearances  have  been  described  by  Elliott  and 
Tuckett,  who  found,  as  others  had  before  them,  that  besides  granules  of 
what  appear  to  be  fat,  a  doubly  refracting  substance  is  found  in  the  cor- 
tical cells  of  most  animals — varying  in  amount  and  in  its  position  in  the 
cortex  in  different  species.  In  some  it  takes  the  form  of  doubly  refract- 
ing crystals.  Elliott  and  Tuckett  regard  both  the  fatty  and  the  aniso- 
tropous  substance  as  products  of  secretion  of  the  cells.  They  find  that 
the  doubly  refracting  substance  increases  in  amount  during  rest  and 
diminishes  as  the  result  of  muscular  activity.  But  they  state  that  in  some 
animals,  e.  g.  the  sheep,  both  substances  may  be  absent.  In  the  guineapig 
there  are  numerous  brown  colored  granules  in  the  cells — chiefly  in  the 
zon a  reticularis — and  Elliott  and  Tuckett  state  that  these  also  accumulate 
during  rest  and  quickly  disappear  with  muscular  work,  fatty  globules 
taking  their  place.  The  doubly  refracting  lipoid  substances  seem  to  con- 
sist  mainly  of  lecithin  and  cholesterin — the  latter  in  the  form  of  esters. 
According  to  Orgler,  they  consist  mainly  of  protagon.  Rosenheim  and 
Tebb,  on  the  other  hand,  extracted  from  the  suprarenal  cortex  of  the 
ox  various  fatty  acids,  cholesterin  esters  and  phosphatides,  such  as 
sphingomyelin,  but  not  free  cholesterin.  It  is  probably  of  cholesterin 
esters  that  the  doubly  refracting  material  is  mainly  composed  (Aschoff). 

The  suggestion  that  the  suprarenal  cortex  may  be  the  chief  seat  of  manu- 
facture of  the  lipoids  of  the  body  and  may  especially  be  related  to  the  formation 
and  development  of  the  myelin  of  the  medullated  nerve  fibres  seems  an  obvious 
one.  And  the  fact  that  in  the  human  foetus  and  infant  so  large  a  develop- 
ment of  suprarenal  cortex  occurs — which  is  missed  in  the  anencephalous  mon- 
ster— seems  to  indicate  a  connexion  between  the  development  of  the  sub- 
stances formed  in  the  cortex  and  those  constituting  the  cerebral  hemispheres. 
But  against  this  idea  we  have  the  further  statement  of  Elliott  and  Armour  that 
in  the  foetus  the  superadded  part  of  the  suprarenal  cortex  does  not  contain 
the  doubly  refracting  lipoid  substances  which  are  characteristic  in  most  animals 
of  the  ordinary  cortical  cells — although  they  speak  of  the  cells  of  the  foetal 
coitex  as  undergoing  a  fatty  change  after  birth.  Nor  does  the  doubly  refracting 


38  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

lipoid  matter  occur  in  all  animals:  in  many  species  it  is  absent  altogether. 
This  is  the  case  with  all  adult  ruminants  examined,  although  it  may  occur  in 
them  in  the  young  state.  Thus  while  absent  in  the  ox  or  cow  it  is  said  to  be 
present  in  small  amount  in  the  calf.  In  both  man  and  animals  where  normally 
present  it  tends  to  disappear  under  various  abnormal  (disease)  conditions: 
whilst  during  pregnancy  lipoids  are  said  to  increase  in  amount,  not  only  in 
the  suprarenals  but  in  all  other  organs  of  the  body. 

The  cortex  increases  in  proportion  to  the  growth  of  the  body  more 
than  the  medulla.  It  varies  in  size  with  the  condition  of  activity  of  the 
sexual  glands  in  animals;  nevertheless,  castration  is  followed  by_hyper- 
trophy  of  the  cortex.  But  there  is  no  evidence  that  any  kind  of  active 
autacoid  substance  is  produced  by  the  cortical  cells,  and  it  is  probable 
that  their  function  is  associated  with  the  building  up  of  metabolic  prod- 
ucts which  are  to  find  employment  in  other  parts  of  the  organism. 


STRUCTURE  OF  THE  MEDULLA  OR  CHROMAFFINE  PART  OF  THE  ADRENALS. 

The  medulla  is  composed  of  cells  which  have  a  different  form  and 
structural  appearance  from  those  of  the  cortex.  They  are  arranged  in 
what  in  section  appear  like  anastomosing  columns  with  spaces  between, 
but  in  point  of  fact  the  medulla  is  better  described  as  a  solid  cell-mass 
permeated  by  sinus-like  capillary  and  venous  spaces.  In  this  respect  it  is 
not  unlike  liver  tissue.  Many  of  the  cells  are  compactly  arranged  around 
vascular  spaces.  They  are  irregularly  polygonal  in  form,  but  where  they 
abut  on  the  sinusoid  spaces  they  often  assume  a  more  columnar  aspect. 
There  can  be  little  doubt  that  the  materials  they  secrete  find 
heir  way  directly  into  the  blood  within  these  spaces.  The  cell 
protoplasm  contains  granules  which  vary  in  amount  in  differ- 
ent cells.  Some  of  these  granules  are  stained  brown  with 
chromic  acid  and  its  salts  (adrenine  or  chromaffine  reaction)  and 
this  gives  a  yellowish-brown  color  to  the  medulla  when  the  suprarenals 
are  fixed  in  any  solution  containing  these  salts.  Occasionally  the  colora- 
tion is  more  diffuse.  A  similar  reaction  is  sometimes  given  by  the  blood 
and  lymph  in  the  vessels  of  the  medulla  in  sections  of  the  organ. 

Besides  the  chromaffine  granules  above  mentioned,  others  are  found, 
somewhat  coarser,  soluble  in  water  and  alcohol  but  not  in  ether,  and 
staining  with  difficulty.  Lipoid  and  pigment  granules  are  also  sometimes 
seen.  The  relationship  of  these  various  granules  to  one  another  is  not 
known.  Those  accessory  glands  which  have  a  similar  structure  and  deriva- 
tion to  the  medulla  of  the  suprarenal  capsules  and  contain  cells  which  are 
colored  brown  by  chromic  acid  are  termed  paraganglia  by  Kohn,  chro- 


THE   ADRENAL   APPARATUS  39 

maphil  bodies  by  Vincent,  chromaffine  bodies  by  most  other  authors* 
This  last  term — although  not  without  objection  on  the  score  of  etymol- 
ogy— has  come  to  be  so  widely  employed  to  express  the  specific  character 
of  the  organs  in  question  that  it  seems  necessary  to  adopt  it. 

All  the  physiological  effects  which  are  about  to  be  described  as 
yielded  by  suprarenal  extracts  are  obtainable  from  extract  of  medulla 
alone :  intravenous  injection  of  extract  of  cortex  gives  no  appreciable  re-  v 
suit.  In  Teleostei,  where  the  cortex  is  represented  by  the  corpuscles  of 
Stannius,  and  in  the  Elasmobranchs,  in  which  the  cortex  is  represented 
by  the  interrenal  body  and  the  medulla  by  the  entirely  separate  ' '  paired 
bodies ' '  of  Balf our,  it  has  been  shown  by  Vincent  that  the  latter  yield 
an  active  extract,  whilst  that  of  the  other  bodies  is  inactive.  It  was  early 
proved  by  Moore  that  the  action  of  the  extracts  of  medulla  is  due  to  the  > 
material  within  the  cells  which  becomes  stained  with  chromic  salts  and 
which  is  readily  oxidized  by  various  reagents,  giving  characteristic  color 
reactions  with  ferric  cholride,  chlorine  water,  and  caustic  alkalines  (Vul- 
pian).  A  similar  reaction  was  obtained  by  Vulpian  with  a  material  con- 
tained in  the  blood  of  the  suprarenal  vein.  This  chromaphil  substance, 
after  being  partly  isolated  by  Frankel,  was  prepared  in  a  condition 
approaching  to  purity  by  v.  Fiirth,  and  by  Abel,  and  eventually  in  a 
crystalline  form  by  Takamine  and  by  Aldrich.  It  has  received  various 
names,  such  as  suprarenin  (v.  Fiirth),  epinephrin  (Abel),  adrenalin 
(Takamine),  the  last  being  that  by  which  it  is  most  widely  known.  But 
as  this  name  has  a  commercial  attachment,  it  is  better  to  employ  the  neu- 
tral expression  adrenine  in  place  of  it.**  It  has  been  estimated  by  Batelli 
that  the  suprarenal  capsules  contain  about  1  part  of  adrenine  per  1,000 
of  the  whole  gland,  but  as  it  only  occurs  in  the  medulla,  which  forms 
less  than  a  fourth  of  the  gland,  the  proportion  in  this  would  be  propor- 
tionately greater. 

Adrenine  can  be  synthetized,  methyl-acetyl-pyrocatechin  being  first 
prepared.  This  when  reduced  gives  a  racemic  salt  which  can  be  split  into 
(i-adrenine  and  ^-adrenine.  The  latter  appears  to  be  in  all  respects  iden- 
tical with  the  natural  product,  while  the  racemic  salt  and  its  dextrorota- 
tory moiety  are  much  less  active  physiologically. 


*The  carotid  gland  is  of  this  nature.  The  coccygeal  gland  is  different.  It 
contains  no  chromaffine  cells  and  appears  to  represent  an  arteriovenous  anas- 
tomosis which  is  met  with  in  certain  lower  mammals.  The  paraganglia  in- 
variably occur  in  close  morphological  and  developmental  connexion  with  sympa- 
thetic nerves  and  ganglia  (Stilling). 

**Chemically  adrenine  is  ortho-dioxyphenol-ethanol-nethylamine  and  is  re- 
lated to  tyrosine. 


40  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

Chromaffine  cells  containing  an  adrenine-like  substance  have  been  found 
in  almost  all  vertebrates,  even  in  Petromyzon.  They  have  also  been  described 
in  the  epithelium  cells  of  the  mantle  in  a  gasteropod  (Purpura  lapillus)  by  Roaf. 
In  Annelids  they  occur,  according  to  Sommet  and  Pol,  in  some  of  the  nerve-cells 
of  the  segmental  ganglia.  This  is  well  seen  in  the  leech,  the  bloodvessels  of 
which  react  to  adrenine  like  those  of  vertebrates.  The  development  of  these 
chromaffine  cells  is,  according  to  J.  F.  Gaskell,  correlated  with  that  of  a  mus- 
cular vascular  system. 

Abel  has  made  the  remarkable  observation  that  certain  patches  of  skin 
glands  in  a  large  American  toad  (Bufo  aqua)  furnish  a  white,  pasty  secretion 
containing  a  large  proportion  of  adrenine. 

VESSELS  AND  NERVES. 

The  bloodvessels  are  very  numerous.  The  arteries  enter  at  the 
capsule  and  give  off  branches  to  supply  the  cortex  with  a  rich  capillary 
network.  The  bloodvessels  do  not  penetrate  the  cell-columns  of  the 
zona  glomerulora  and  zona  fasiculata  of  the  cortex,  but  run  in  the  con- 
nective tissue  septa  between  them.  In  the  zona  reticularis  the  capillaries 
are  large,  have  a  sinusoid  character  and  come  into  very  close  relationship 
to  the  cells.  They  pass  into  the  sinusoids  of  the  medulla.  According  to 
Neumann,  the  bloodsupply  of  the  suprarenal  is  more  abundant  than  that 
of  any  other  organ  in  the  body,  viz.,  as  much  as  6  to  7  c.  c.  per  gramme 
and  per  minute  with  a  bloodpressure  of  130  m.  Hg.  This  is  even  higher 
than  that  of  the  thyroid,  which  comes  next  with  5  c.  c.  per  gramme  and 
per  minute.  The  respiratory  exchange  is  also  very  high  (Baumann). 

In  birds  and  reptiles  the  suprarenals  have  a  venous  bloodsupply  as 
well  as  an  arterial — blood  being  conveyed  to  each  gland  by  a  "portal" 
vein  which  is  usually  formed  by  the  junction  of  two  or  three  intercostal 
veins.  The  connective  tissue  septa  of  the  cortex  also  contain  lymphatics, 
which,  like  the  blood  capillaries,  pass  directly  into  the  vessels  of  the 
medulla. 

The  suprarenals  are  very  richly  supplied  with  nerves.  Each  supra- 
renal receives  no  less  than  thirty- three  nervous  filaments  (Kolliker)  de- 
rived partly  direct  from  the  splanchnic,  partly  from  the  suprarenal  plex- 
us, which  is  itself  constituted  by  branches  from  the  coeliac,  phrenic  and 
renal  plexuses.  After  forming  a  network  in  the  connective  tissue  capsule, 
the  nerves  penetrate  into  the  cortex,  partly  supplying  its  bloodvessels, 
partly  its  cell-columns.  But  most  of  the  nerves  extend  to  the  medulla, 
wh.ere  they  form  a  dense  plexus  from  which  filaments  pass  to  end  be- 
tween the  secretory  cells.  Groups  of  sympathetic  nerve-cells  are  occa- 
sionally found  both  in  the  medulla  and  in  the  deeper  parts  of  the  cortex. 


THE  ADRENAL  APPARATUS  41 

EFFECTS  OF  SUPRARENAL  REMOVAL:     EPINEPHRECTOMY. 

Addison's  account  of  the  disease  he  described  and  which  he  termed 
"idiopathic  anaemia"  led  Brown-Sequard  (1856)  to  test  the  effect  of  the 
removal  of  the  suprarenal  glands  in  animals.  The  operation,  which  was 
performed  upon  a  number  of  animals  of  different  species  (rabbits,  guinea- 
pigs,  dogs  and  cats),  was  followed  in  every  case  of  double  extirpation  by 
a  fatal  termination  within  thirty-seven  hours  of  the  removal.  But  a 
fatal  result  was  produced  also  in  all  or  nearly  all  the  animals  in  which 
the  lesion  was  unilateral,  although  subsequently  Brown-Sequard  suc- 
ceeded in  keeping  some  animals  alive  for  a  few  days  when  only  one 
capsule  was  removed.  Since  it  is  now  well  established  that  careful  removal 
of  one  capsule  under  aseptic  precautions  is  seldom  fatal,*  there  can  be 
little  doubt  that  Brown-Sequard 's  results  were  in  considerable  measure 
the  consequence  of,  or  at  any  rate  were  complicated  by,  shock  and  sepsis, 
and  that  they  could  not  be  relied  on  as  a  proof  that  the  suprarenal  cap- 
sules are  essential  to  life.  This  is  indeed  the  opinion  which  was  formed 
by  most  of  his  contemporaries.  Nevertheless,  looked  at  in  the  light  of 
our  present  knowledge,  it  is  certain  that  death  must  have  been  either 
caused  or  greatly  accelerated  by  the  removal  of  both  capsules — since  this 
is  now  known  to  be  in  most  animals  the  invariable  result  of  the  double 
operation  and  occurs  within  a  few  days.  There  are,  however,  exceptions, 
especially  in  some  species  of  animals :  among  which  the  white  rat  may  be 
particularly  mentioned.  These  exceptions  are  probably  associated  with 
the  occurrence  of  accessory  bodies,  but  whether  these  must  be  of  cortical 
or  medullary  nature — or  both — is  not  determined. 

No  effect  of  the  extirpation — especially  if  the  operation  be  performed 
on  the  two  glands  at  an  interval  of  a  few  days — is  at  first  apparent.  For 
some  days  there  is  little  sign  of  anything  wrong.  Then  the  animal  be- 
comes less  lively  and  exhibits  signs  of  muscular  weakness.  The  body 
temperature  also  becomes  lowered.  Soon  the  weakness  becomes  extreme, 
the  pulse  feeble,  the  bloodpressure  low,  and  the  respiration  dyspnoeic. 
Death  soon  follows,  sometimes  immediately  preceded  by  convulsions. 

Experiments  on  adrenal  transplantation  have  for  the  most  part  led 
to  negative  results.  The  graft  almost  invariably  undergoes  necrosis  and 
disappears,  although  in  some  cases  the  cortical  part  has  seemed  to  take 
for  a  time.  Administration  of  suprarenal  extract  is  unable  either  in  Addi- 


*An  exception  must  be  made  for  the  guineapig  in  which  unilateral  extirpa- 
tion is  frequently  followed  by  death.  It  may  be  remarked  that  the  suprarenals 
are  larger  in  proportion  to  its  size  in  the  guineapig  than  in  any  other  animal. 


42  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

son's  disease  or  in  the  cachexia  produced  by  extirpation,  to  prevent  the 
usual  fatal  termination,  although  this  may  be  somewhat  deferred.  The 
muscular  weakness  characteristic  of  Addison's  disease  may  for  a  time 
tend  to  disappear  with  the  administration,  so  that  the  ergographic  record 
may  again  approach  the  normal.  But  such  administration  cannot,  as  in 
the  case  of  cachexia  thyreopriva,  take  the  place  of  the  internal  secretion 
of  the  gland,  and  until  measures  are  found  to  induce  an  implanted  organ 
to  grow,  Addison's  disease  will  probably  continue  to  terminate  fatally. 
With  the  progress  of  surgery,  however,  and  especially  the  adoption  of 
the  methods  of  Carrel,  the  possibility  of  successful  implantation  seems 
less  hopeless  than  was  the  case  only  a  few  years  ago. 

After  extirpation  of  one  gland  only  there  is  a  compensating  hyper- 
trophy of  the  other,  and  also  of  the  accessory  bodies.  Castrated  animals 
were  found  by  Hultgren  and  Andersson  to  live  much  longer  after  the 
complete  operation  than  normal  individuals.  This  is  also  stated  to  be  the 
case  if  the  complete  operation  is  performed  in  two  stages,  first  the  capsule 
of  the  one  side  and  then  that  of  the  other  being  removed.  This  result  is 
perhaps  due  to  hypertrophy  of  accessory  bodies.  With  regard  to  the 
total  amount  of  suprarenal  substance  that  must  remain  in  order  to  main- 
tain life,  Biedl  found  that  in  cats,  dogs  and  rabbits  if  one-eighth  of  the 
whole  suprarenal  substance  is  left  the  animals  always  survive.  He  con- 
cludes, after  a  survey  of  all  the  experimental  evidence  on  the  subject, 
that  it  is  abundantly  proved  that  "the  suprarenals  are  not  only  im- 
portant but  are  essential  to  life,"  and  that  it  is  probable  that  this  is  due 
to  some  material  yielded  by  the  cortex — although  the  loss  of  the  adrenine 
which  is  supplied  by  the  medulla  may  be  contributory. 

It  appears  that  in  other  diseases  than  Addison's  the  functions  of 
the  suprarenal  capsules  may  to  a  great  extent  become  suppressed.  In 
diphtheria,  whether  natural  or  produced  experimentally  in  animals,  it 
has  been  found  that  the  amount  of  adrenine  yielded  by  the  medulla  of 
the  suprarenals  is  markedly  diminished  and  may  even  in  extreme  cases 
disappear  altogether.  In  cholera  also  the  amount  is  greatly  diminished, 
and  it  is  stated  that  in  this  disease  subcutaneous  administration  of 
adrenine  is  markedly  beneficial.  If  the  diminution  in  the  amount  of 
adrenine  formed  should  be  proved  to  hold  good  in  other  acute  infectious 
disorders,  it  would  seem  not  improbable  that  the  interference  with  the 
functions  of  the  suprarenal  capsules  is  in  large  measure  the  cause  of  the 
muscular  and  cardiac  weakness  and  general  loss  of  tone  which  are  promi- 
nent symptoms  in  these  affections. 


THE  ADRENAL  APPARATUS  43 

EFFECTS  OF  ADMINISTRATION  OF  SUPRARENAL  EXTRACTS. 

If  an  extract  or  decoction  of  suprarenal  capsule — made  with  wator 
or  Ringer's  solution — is  injected  into  the  vein  of  an  animal,  the  most 
striking  result  obtained  is  an  immediate  and  marked  rise  of  blood-pressure 
(Oliver  and  Schafer,  1894).  This  can  be  shown  to  be  caused  by  con- 
traction of  the  peripheral  arteries.  Along  with  this  contraction  a  slowing 
of  the  heart's  action  may  occur  due  to  an  effect  on  the  cardio-inhibitory 
center  and  may  somewhat  limit  the  rise  of  blood-pressure.  But  if  the 
vagi  are  cut,  or  paralyzed  by  atropine,  the  heart  beats  become  enormously 
accelerated  and  also  augmented  in  force  (primarily  by  the  action  of  the 
autacoid  on  the  auricles,  but  also  somewhat  on  the  ventricles*),  and  this 
greatly  increases  the  rise  of  blood-pressure.  There  is  some  diminution  in 
the  force  of  the  respirations  and  occasionally  a  temporary  cessation  of 
breathing,  especially  in  the  rabbit.  But  this  disappears  long  before  the 
effect  on  the  bloodvessels  has  ceased  to  show  itself.  The  effect  upon  the 
vessels  lasts  a  few  minutes,  gradually  passing  off:  after  its  passage  the 
blood-pressure  is  usually  a  little  lower  than  before.  The  arteries  which 
are  most  affected  are  those  of  the  splanchnic  area:  those  of  the  limbs 
and  trunk  rather  less,  although  the  cutaneous  vessels  are  usually  strongly 
contracted :  those  of  the  pulmonary  system  and  of  the  brain  only  very 
slightly  if  at  all,  and  those  of  the  coronary  circulation  not  at  all:  indeed, 
in  some  animals  these  last  are  dilated  by  the  extract.  According  to  Bar- 
bour,  the  human  coronary  arteries  are  constricted,  whilst  those  of  the 
calf,  sheep,  pig  and  other  mammals  are  dilated  (inhibited).  It  is  always 
the  smaller  vessels  which  are  most  affected  and  in  consequence  of  the 
great  rise  of  pressure  which  their  contraction  produces  the  larger  arteries 
tend  to  become  passively  dilated :  this  dilatation  may  be  very  great.  The 
effect  upon  the  vessels  is  seen  after  complete  destruction  of  the  central 
nervous  system  and  after  severance  of  the  nerves  to  the  part :  indeed,  even 
after  the  nerves  to  the  vessels  have  been  severed  for  a  long  time.  It  is 
therefore  due  to  a  direct  action  of  the  autacoid  principle  of  the  gland 
upon  the  contractile  tissue.  Nevertheless,  such  action  only  occurs  in  the 
case  of  suprarenal  extract  in  tissues  which  are  supplied  with  nerves  from 
the  sympathetic  system,  and  in  the  embryo  in  such,  tissues  only  after  they 
have  received  their  nerve  supply.  And,  as  has  just  been  stated,  severance 
of  the  nerves,  so  far  from  stopping  the  action,  tends  on  the  contrary  to 
make  the  tissues  supplied  by  the  severed  nerve  more  easily  excited  by  the 
autacoid**.  Gunn  and  Chavasse  have  shown  that  adrenine  has  also  an 


*In  birds,  as  Paton  has  shown,  the  augmentation  is  confined  to  the  auricles. 
**This  has  been  found  to  apply  not  only  to  the  bloodvessels  but  also  to  the 
pupil  (Meltzer  and  Auer)  and  to  the  retractor  penis  (Fletcher),  and  is  probably 
of  general  application. 


44  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

action  upon  the  muscular  coat  of  veins,  causing  tonic  contraction  in  the 
case  of  peripheral  veins  and  rhythmic  contraction  in  the  case  of  the 
superior  vena  cava  near  the  heart. 

If  the  amount  of  injected  extract  be  great,  the  rise  of  blood-pressure  caused 
by  vascular  contraction  and  heart  acceleration  may  be  enormous — three  or  four 
times  the  normal — and  the  amount  of  strain  put  on  the  heart  is  correspondingly 
great.  Sometimes  the  heart  muscle  is  unable  to  respond  properly  under  these 
circumstances  andMhe  ventricular  action  becomes  fibrillar — delirium  cordis  being 
produced,  generally  leading  to  instant  death.  This  seems  especially  liable  to  occur 
in  a  particular  phase  of  early  chloroform  anaesthesia  (Levy).  But  as  a  general 
rule  a  number  of  successive  injections  can  be  made  into  a  vein  and  each  one  will 
produce  an  amount  of  rise  of  blood-pressure  proportionate  to  the  amount  of  auta- 
coid  in  the  extract:  the  activity  of  extracts  can  in  fact  be  gauged  by  this  method. 
Other  modes  of  testing  the  activity  of  suprarenal  extracts  are  (1)  by  their  action 
when  added  to  Ringer's  solution  perfused  through  the  bloodvessels  of  a  frog  the 
central  nervous  system  of  which  has  been  destroyed,  (2)  by  the  effect  pro- 
duced upon  the  pupil  of  the  excised  eye  of  a  frog  when  immersed  in  Ringer's 
solution  to  which  a  definite  amount  of  the  extract  is  added,  (3)  immersion  of  the 
excised  uterus  of  a  rat  in  a  similar  solution  kept  aerated  by  a  stream  of  oxygen, 
(4)  the  same,  but  using  a  piece  of  intestine  instead  of  uterus,  and  (5)  the  same, 
but  using  strips  of  artery. 

The  effect  of  suprarenal  extract  upon  the  heart  and  vessels  is  not 
the  only  action  upon  plain  muscle,  although  it  is  the  most  obvious.  Other 
involuntary  muscular  tissue  supplied  by  sympathetic  fibres  is  also 
affected.  This  may  be  in  the  direction  of  increased  contraction  (spleen, 
vagina,  uterus*,  vas  deferens,  retractor  penis),  or  of  inhibition  (intes- 
tine, stomach,  oesophagus,  gall-bladder**).  Certain  of  the  plain  mus- 
cles of  the  orbit  and  globe  of  the  eye  are  also  excited  so  that  the  eye 
tends  to  protrude  and  the  palpebral  fissure  appears  to  enlarge :  the  third 
eyelid  is  retracted  and  the  pupil  widely  dilated  (Lewandowsky).*** 

A  flow  of  saliva  similar  to  that  caused  by  excitation  of  the  cervical 
sympathetic  is  also  produced  and  is  accompanied  by  contraction  of  the 
vessels  of  the  glands :  the  flow  of  saliva  is  little  apparent  in  the  dog,  but 


*Cushaly  has  shown  that  the  uterus  of  a  pregnant  case  is  contracted  by 
adrenine  whilst  the  virgin  and  non-pregnant  uterus  is  usually  inhibited. 

**In  some  animals  (e.  g.  ferret)  the  urinary  bladder  is  contracted  by  supra- 
renal extract;  in  others  it  is  relaxed  (Elliott).  This  again  corresponds  with  the 
effect  of  stimulating  the  sympathetic  nerves  passing  to  that  viscus, 

***Dropping  a  solution  of  adrenine  into  the  conjunctival  sac  does  not  pro- 
duce dilatation  of  the  pupil  unless  the  superior  cervical  ganglia  of  the  sympa- 
thetic have  been  previously  removed.  This  causes  the  dilatator  pupillse  to  be 
more  sensitive  to  the  action  of  the  autacoid  (see  above).  It  has  also  been  no- 
ticed that  in  diabetes — especially  when  associated  with  pancreatic  disease  or 
extirpation — the  pupil  will  react  to  the  instilled  solution  (Lowi). 


THE   ADRENAL   APPARATUS  45 

it  is  well  marked  in  the  cat,  in  which  animal,  as  is  well  known,  excitation 
of  the  sympathetic  in  the  neck  provokes  an  abundant  flow  from  the  sali- 
vary glands.  The  lacrimal  glands  are  caused  to  secrete.  Some  influence 
is  exerted  upon  the  contraction  of  skeletal  muscle,  the  curve  of  which  is 
prolonged,  although  the  latency  is  not  increased.  The  effect,  therefore,  is 
not  one  of  fatigue,  but  of  increased  excitability.  The  autacoid  has  fur- 
ther been  found  to  defer  the  onset  of  fatigue  of  muscle  and  to  assist  its 
recovery.  The  arrectores  pilorum,  especially  those  of  certain  parts  of 
the  trunk,  are  stimulated  to  contract.  As  a  rule  there  is  no  increase  of 
sweat  secretion.  Adrenine  also  causes  contraction  of  the  pigment  cells 
both  of  the  skin  and  retina  of  the  frog.  It  is  noteworthy  that  sympathetic 
stimulation  also  produces  this  effect,  at  least  this  is  so  for  the  pigment 
cells  of  the  skin.  In  birds  some  of  the  effects  are  different  from  those 
obtained  in  mammals.  Thus  in  the  duck  the  effect  of  adrenine  is  to  cause 
decrease  in  the  strength  of  the  ventricular  beats,  which  may  more  than 
compensation  for  the  arterial  contraction  produced  (Noel  Paton  and 
Watson).  There  is  also  contraction  of  the  intestine  instead  of  inhibition. 
Although  the  rule  is  perhaps  not  entirely  without  exception,  it  may  be 
stated  as  a  general  principle  that  the  result  of  suprarenal  injection  is 
identical  with  that  of  stimulating  the  endings  of  the  sympathetic  nerves 
throughout  the  body  (Langley).  It  has  been  found  by  Dixon  that  if  the 
endings  of  the  sympathetic  are  paralyzed  by  apocodein  adrenine  is  with- 
out action  on  the  paralyzed  parts.  Apocodein  is  known  to  have  the  same 
effect  upon  the  results  of  sympathetic  stimulation. 

As  has  already  been  pointed  out,  the  above  results  are  obtained  even 
if  the  sympathetic  nerves  have  been  divided  and  allowed  to  undergo  de- 
generation. It  has,  therefore,  been  concluded  that  under  the  influence  of 
these  nerves  the  tissues  produce  either  at  the  junction  of  nerve  and  mus- 
cle (myo-neural  junction  of  Elliott)  or  throughout  the  cell-protoplasm  a 
material  ("receptive  or  excitable  substance"  of  Langley)  which  reacts 
with  adrenine,  and  not  only  with  it  but  also  with  other  drugs,  such  as 
certain  alkaloids  which  have  a  pronounced  physiological  action.  And 
furth.er,  that  this  receptive  substance  increases  either  in  amount  or  sensi- 
tivity after  the  action  of  the  nerves  is  withdrawn  by  their  severance. 

A  very  minute  dose  of  the  active  substance  may,  as  Moore  and  Purinton 
showed,  produce  the  reverse  action  upon  the  bloodvessels,  viz.,  dilatation  instead 
of  contraction.  Abolition  of  the  effect  of  adrenine  in  producing  contraction  of 
plain  muscle  (and  the  same  applies  to  the  effects  of  sympathetic  excitation)  can, 
as  Dale  has  shown,  be  obtained  by  exhibition  of  ergotoxin — an  amine  base  ob- 
tained from  ergot  and  also  obtainable  from  the  products  of  breaking  down  of 
histodine.  Ergotoxin  does  not,  however,  paralyze  the  inhibition-producing  effect 
of  adrenine  (or  that  of  sympathetic  excitation).  Therefore,  if,  as  sometimes  hap- 


46  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

pens,  both  contraction  and  inhibition  can  normally  be  brought  about  through  the 
sympathetic  and  also  by  adrenine,  when  the  contraction  effect  is  abolished  by 
ergotoxin,  the  inhibition  effect  alone  appears,  and  this  may  produce  a  reversal  of 
the  normal  action.  Thus  after  a  sufficient  dose  of  ergotoxin,  adrenine  produces 
vaso-dilatation  in  place  of  vaso-construction,  and  inhibition  of  uterine  contrac- 
tions instead  of  increased  contraction.  Ergotoxin  doubtless  acts,  like  adrenine, 
on  the  neuro-muscular  junctional  or  receptive  substance. 

The  action  of  adrenine  upon  the  terminal  apparatus  of  the  sympathetic 
system  is  common  to  a  number  of  primary  and  secondary  amines:  the  action  has 
been  termed  "sympatho-mimetic"  by  Barger  and  Dale.  The  more  nearly  the 
structure  of  the  amine  approaches  that  of  adrenine  the  more  marked  is  this 
action.  A  knowledge  of  these  facts  has  led  to  the  production  of  other  syn- 
thetic drugs  having  similar  properties.  The  chemical  history  of  adrenine  fur- 
nishes indeed  a  striking  illustration  of  the  drug-like  character  of  the  autacoid 
substances  produced  by  the  endocrine  organs. 

Eepeated  intravenous  injections  into  the  ear-vein  given  at  intervals 
of  a  few  days  produce  (in  the  rabbit)  degenerative  sclerosis  of  arteries 
(Josue).  This  action  is  not  specific  to  the  suprarenal  autacoid,  but  is 
the  result  of  prolonged  abnormally  high  blood-pressure,  whether  produced 
by  autacoids  or  by  drugs  or  in  any  other  way. 

Local  application. — Applied  directly  to  the  smaller  bloodvessels,  the 
suprarenal  autacoid  produces  marked  contraction  of  the  muscular  coat 
(Oliver)  and  it  is  therefore  of  value  in  surgery  as  a  styptic  for  arresting 
haemorrhage  from  small  arteries. 

Effects  of  subcutaneous  injection. — Subcutaneous  injection  of  the 
extract  does  not  produce  the  rapid  effect  on  involuntary  muscle  which  is 
so  characteristic  of  intravenous  injection — although,  as  Meltzer  and  Auer 
have  shown,  intramuscular  injection  may  show  this  result.  But  large 
doses  of  the  extract  or  of  the  separated  autacoid  substance  of  the  medulla 
produce  in  rabbits  and  some  other  animals  serious  or  even  fatal  symp- 
toms, probabiy  by  causing  extreme  contraction  of  the  arterioles  of  the 
central  nervous  system.  After  a  period  of  excitement,  with  rapid  pulse 
and  respirations,  a  period  of  depression  supervenes.  Accompanying  this' 
depression,  the  muscular  movements  are  first  slowed:  there  is  then 
paralysis  of  the  limbs  and  later  of  the  respiratory  muscles,  with  asphyxial 
convulsions.  The  body  temperature  becomes  lowered  some  little  while 
before  death.  The  paralysis  is  central.  Post  mortem  a  general  hyper- 
aemia  of  the  viscera  is  evident  and  abundant  haemorrhages  are  seen  to 
have  occurred  in  various  parts.  If  a  first  dose  is  not  fatal,  a  certain 
amount  of  immunity  may  be  produced  to  a  subsequent  dose  (Vincent). 
The  injection  also  invariably  produces  glycosuria  (Blum),  even  if  the 
animal  has  been  fed  on  a  diet  free  from  carbohydrates  (Noel  Paton). 


THE   ADRENAL  APPARATUS  47 

This  appears  due  in  part  to  an  action  on  the  liver-cells,  in  part  to  an 
effect  on  the  pancreas:  for,  as  Herter  and  Wakeman  have  found,  the 
direct  application  of  the  autacoid  to  the  pancreas  will  cause  glycosuria. 
This  will  be  again  referred  to  in  considering  the  influence  of  the  supra- 
renal on  other  glands  and  in  connexion  with  the  internal  secretion  of 
the  pancreas. 

Considerable  amounts  of  the  extract  can  be  taken  into  the  stomach 
without  producing  any  marked  physiological  result.  This  is  probably 
due  to  the  fact  that  the  active  material  is  destroyed  almost  as  fast  as  it  is 
absorbed.  That  such  destruction  is  readily  produced  is  obvious  from  the 
fact  that  even  when  large  doses  are  injected  into  a  vein  the  effects  pass 
off  within  a  few  minutes.  Where  the  active  substance  becomes  destroyed 
is  not  known,  although  it  has  been  conjectured  that  it  may  be  in  the 
tissues  generally,  especially  the  muscles  and  liver.  The  passing  off  of  the 
effect  may  in  part  also  be  due  to  a  fatigue  of  the  excited  tissues,  render- 
ing them  less  responsive.  For  it  is  affirmed  that  the  active  principle  does 
not  at  once  disappear  from  the  blood,  but  may  be  detected  by  testing  this 
fluid  on  another  animal.  This  statement  is,  however,  denied  by  Tren- 
delenburg.  Meltzer  finds  that  adrenine  is  destroyed  by  cerebrospinal 
fluid.  ( It  was  shown  by  Oliver  and  Schaf er  not  to  be  destroyed  by  blood 
nor  eliminated  by  the  urine.)  It  has  been  found  by  W.  Cramer  that  the 
autacoid  is  rapidly  inactivated  in  vitro  by  dilute  formaldehyde,  and  it 
may  well  be  that  the  inactivation  in  vivo  is  brought  about  by  contact  with 
metabolism  products  which  have  a  similar  action. 

Influence  of  nerves  on  the  secretion  of  adrenine  by  the  suprarenal 
capsules. — It  was  shown  by  Biedl  that  the  stimulation  of  the  splanchnic 
nerves  is  accompanied  by  an  increased  bloodflow  through  the  organ. 
The  result  is  even  better  marked  when  these  nerves  have  been  cut  and 
allowed  to  degenerate  for  two  or  three  days  so  that  only  the  vaso-dilators 
are  acting.  Tscherboksaroff,  in  confirmation  of  an  observation  by  Dreyer, 
found  that  during  excitation  of  the  splanchnic  in  a  dog  the  blood  passing 
from  the  suprarenal  capsule  by  its  vein  produces  a  greater  effect  in  rais- 
ing the  blood-pressure  of  another  dog  than  the  blood  of  the  suprarenal 
vein  under  ordinary  circumstances,  and  concluded  that  adrenine  is  passed 
into  the  traversing  blood  under  the  influence  of  impulses  conveyed  by 
these  nerves.  He  also  found  a  larger  amount  of  adrenine  in  the  supra- 
\  renal  capsules  after  the  stimulation.  But  the  actual  proof  of  secretion 
under  the  influence  of  nerves  is  most  satisfactorily  furnished  by  the 
experiment  of  Asher,  who  found  that  after  ablation  of  the  stomach  and 
intestines  and  all  the  other  abdominal  organs,  stimulation  of  the  splanch- 
nics  causes  a  marked  rise  of  blood-pressure,  which  fails  if  the  suprarenal 


48  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

bloodvessels  are  compressed.  Elliott  and  Tuckett  were  able  to  exhaust  the 
suprarenal  of  its  adrenine  by  stimulation  of  its  nerves  and  Pende  found 
that  section  of  the  splanchnics  leads  eventually  to  atrophy  of  the  medulla. 
According  to  Ehrmann,  the  secretion  is  uninfluenced  by  atropine  or  pilo- 
carpine,  which  affect  most  of  the  external  secretions. 

That  the  passage  of  adrenine  into  the  blood  is  always  proceeding  in 
sufficient  amount  appreciably  to  raise  the  tone  of  the  bloodvessels  seems 
somewhat  doubtful.  Oliver  and  Schafer  found  that,  even  in  the  blood  of 
the  suprarenal  vein,  there  is  not  always  enough  to  cause  a  rise  of  blood- 
pressure  when  a  few  c.  c.  are  injected  into  a  vein.  .  But  it  is  possible  by 
employing  more  delicate  physiological  tests — e.  g.  the  reaction  with  the 
enucleated  eye  of  the  frog  or  by  passing  extracts  of  the  dried  and  depro- 
teinized  blood  through  the  bloodvessels  of  the  frog — to  obtain  evidence  in 
some  animals  of  its  presence  not  only  in  the  blood  of  the  suprarenal  vein, 
but  to  a  less  degree  in  the  blood  generally.  The  amount  is,  however,  nor- 
mally very  small,  even  in  the  former :  not  more  than  about  one  part  in  a 
million,  according  to  Hoskins,  McClure  and  O'Connor.  This  indicates 
that  the  rate  of  passage  into  the  blood  is  usually  slow :  probably  it  varies 
at  different  times.  If  a  very  small  percentage  be  present,  the  blood- 
pressure  may  be  lowered  instead  of  raised.  We  cannot,  therefore,  assume 
that  the  normal  tone  of  the  vascular  system  depends  on  adrenine  in  the 
blood,  although  that  the  maintenance  of  vascular  tone  is  in  some  animals 
assisted  in  this  manner  is  shown  by  the  experiment  of  compressing  the 
suprarenal  vein.  Such  compression  may  be  followed  by  a  considerable 
fall  of  blood-pressure,  which  quickly  recovers,  and,  indeed,  more  than 
recovers,  its  former  height  on  relieving  the  compression.  Temporarily 
compressing  the  abdominal  aorta  produces  somewhat  similar  results.  It 
is  possible  that  the  partially  resumed  tone  of  peripheral  vessels  which 
comes  on  after  section  of  their  nerves  may  be  due  to  an  increase  of 
adrenine  in  the  blood,  perhaps  assisted  by  an  increase  of  the  autacoid  of 
the  posterior  lobe  of  the  pituitary  body.  We  must  also  take  into  consid- 
eration the  circumstance  that  after  section  of  the  nerves  to  plain 
muscle  this  tissue  becomes  much  more  sensitive  to  the  influence  of 
adrenine. 

Trendelenburg  estimated  the  amount  of  adrenine  in  the  blood  of  the  supra- 
renal vein  of  a  cat  and  found  that  on  the  average  .003  mg.  was  passed  out  of  the 
two  organs  per  minute.  From  the  data  thus  obtained  he  reckons  that  about  5  mg. 
per  kilo  body  weight  is  formed  in  24  hours.  After  draining  off  a  large  quantity 
of  blood  and  causing  a  considerable  fall  of  blood-pressure,  the  amount  of  adrenine 
passed  per  minute  was  not  increased.  G.  N.  Stewart  states  that  nerve  massage 
of  the  suprarenals  leads  to.  the  passage  of  an  increased  quantity  of  adrenine  into 
the  blood:  when  the  massage  is  light  a  depressor  effect  is  caused,  when  vigorous 


THE   ADRENAL   APPARATUS  49 

a  pressor  effect;  but,  according  to  Hoskins  and  McClure,  never  so  large  a  pressor 
effect  as  with  "ordinary  therapeutic  dosage."* 

Von  Aurep  finds  that  stimulation  of  the  splanchnic  produces  a  double 
rise  of  blood-pressure ;  the  first  being  due  to  direct  stimulation  of  the  vaso- 
motors,  the  second  to  the  outpouring  of  adrenine  into  the  blood.  This 
latter  phase  fails  to  appear  if  the  suprarenals  are  extirpated.  In  the  cat 
Cannon  found  that  dilatation  of  the  pupils  and  upstanding  of  the  fur 
which  accompany  sudden  alarm  or  excitement  are  associated  with  an 
increased  outpouring  of  adrenine  into  the  blood,  and  he  has  drawn  atten- 
tion to  the  fact  that  many  of  the  phenomena  which  characterize  violent 
emotional  states  (both  in  animals  and  man)  are  similar  to  those  which  are 
produced  by  excess  of  the  suprarenal  autacoid  in  the  blood.  It  would 
further  appear  that  the  glycaemia  and  glycosuria  which  result  from  Ber- 
nard's sugar  puncture  is  accompanied  by  and  probably  largely  due  to  the 
passage  of  an  excess  of  adrenine  into  the  blood,  causing  increased  trans- 
formation of  the  liver  glycogen  into  glucose. 

Section  of  the  splanchnics  diminishes  the  amount  of  adrenine  which 
is  passed  into  the  blood:  according  to  Elliott,  it  is  only  the  reflex  secretion 
which  is  affected ;  an  automatic  solution  goes  on  all  the  time. 

Dale  and  Laidlaw,  and  Cannon  and  Burger,  have  shown  that  it  is 
highly  probable  that  certain  alkaloids  (e.  g.  nicotine  and  pilocarpine) 
exert  their  action  on  involuntary  muscle,  not  directly  but  by  stimulating 
the  suprarenals  to  increased  activity.  This  has  also  been  shown  to  be  the 
case  for  morphia,  chloroform  and  ether  by  Elliott  and  to  be  brought  about 
through  the  splanchnic  nerves. 

RELATIONS  OF  THE   ADRENALS  TO   OTHER   GLANDS  AND  INTERNAL   SE- 
CRETIONS. 

Ott  and  Scott  state  that  various  organ  extracts  produce  an  in- 
creased secretion  of  adrenine  into  the  blood,  viz.,  thyroid,  parathyroid, 
pituitary,  thymus,  pancreas,  testicle  and  ovary.  The  variety  of  these 
would  seem  to  indicate  that  such  effect  can  hardly  be  indicative  of  a 
specific  relationship.  On  the  other  hand,  the  secretion  of  the  adrenals 
has  an  influence  upon  many  diverse  organs  and  glands — including  the 
other  ductless  glands — seeing  that  the  autacoid  secreted  by  the  medulla 
activates  sympathetic  nerve-endings  throughout  the  body. 


*It  may  here  be  mentioned  that  so  small  an  addition  to  the  blood  of  a  dog 
as  .005  mg.  to  1  liter  of  blood  (equal  1  part  in  20  millions)  is  sufficient  to  pro- 
duce a  distinct  rise  of  pressure.  The  same  strength  of  solution  of  adrenine  is 
sufficient  to  dilate  the  pupil  of  the  excised  eye  of  the  frog. 


50  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

With  the  sexual  glands. — A  direct  relationship  between  the  develop- 
ment of  the  sexual  glands  and  that  of  the  suprarenals  may  be  regarded 
as  well  established,  although  the  nature  of  the  relationship — whether 
through  the  nervous  system  or,  as  is  more  probable,  through  chemical 
agencies — is  not  precisely  known.  The  connexion  appears  to  be  more 
with  the  cortex  of  the  adrenals  than  with  the  medulla.  During  preg- 
nancy the  whole  gland  undergoes  enlargement:  this  change  affects  the 
cortex  much  more  than  the  medulla.  Whilst  hypertrophy  of  the 
cortex  is  stated  to  occur  as  the  result  of  castration,  various  observers 
have  found  that  it  is  also  associated  with  sexual  precocity.  Further, 
in  diseased  conditions  resulting  in  hypoplasia  of  the  adrenals,  changes 
in  the  testicles,  especially  in  their  interstitial  cells,  have  been  noted. 
On  the  other  hand,  Elliott  and  Tuckett  deny  connexion  between  the 
suprarenals  and  the  sexual  glands.  They  associate  the  cortex  more 
particularly  with  the  development  of  the  muscular  system:  they  also 
point  out  that  the  lower  the  animal  in  the  vertebrate  or  at  any  rate  in 
the  mammalian  series  the  greater  is  the  relative  development  of  the 
cortex.  More  than  one  observer  has  drawn  attention  to  the  similarity  of 
appearance  between  the  cells  of  the  cortex  of  the  suprarenals  and  those 
of  the  corpus  lute'um,  but  there  is  at  present  no  evidence  of  either 
morphological  or  functional  relationship  between  these  organs. 

With  other  glands. — Injection  of  suprarenal  extract  was  found  by 
Langley  (in  the  cat)  to  produce  an  active  secretion  of  all  the  salivary 
and  mucous  glands  of  the  mouth,  gullet  and  trachea.  The  secretion  is 
not  arrested  by  small  doses  of  atropine  and  is  similar  to  that  produced 
by  sympathetic  excitation.  The  lacrimal  glands  are  also  stimulated  to 
active  secretion:  and  this  is  said  by  Yakawa  to  be  the  case  with  the 
gastric  glands  as  well. 

With  the  liver. — The  secretion  of  bile  is  increased  by  adrenine. 
But  the  most  noteworthy  effect  on  this  organ  is  upon  its  glycogenic 
function,  for  the.autacoid  of  suprarenal  medulla  even  in  small  doses 
produces  a  rapid  conversion  of  the  liver  glycogen  into  sugar,  which 
passes  into  the  blood  and  eventually  into  the  urine.  The  effect  is 
similar  to  that  caused  by  Bernard's  sugar  puncture  of  the  medulla 
oblongata  and  by  excitation  of  the  splanchnics.  On  the  other  hand, 
after  section  of  the  splanchnics  Bernard  found  that  puncture  of  the 
medulla  oblongata  fails  to  cause  glycosuria.  These  effects  on  the  liver 
are  probably  in  large  measure  if  not  entirely  due  to  excitation  of  the 
sympathetic  fibres  passing  to  the  suprarenals,  causing  the  outpouring 
of  an  excess  of  adrenine  into  the  blood  and  this  again  excites  the 


THE   ADRENAL   APPARATUS  51 

terminal  apparatus  of  the  sympathetic  nerves  in  the  liver-cells.  Kahn 
noticed  that  if  one  adrenal  be  left  its  medulla  shows  indications  of  over- 
activity  and  far  less  adrenine  is  stored  within  it  than  normally.  He 
states  that  in  the  guineapig  the  blood  can  be  shown  to  contain  an  ex- 
cess of  adrenine  after  the  sugar  puncture.  In  confirmation  of  this 
A.  Mayer  found  that  Bernard's  puncture  is  not  effective  after  removal 
of  the  adrenals.  Macleod  and  Pearse  have  observed  that  adrenine  pro- 
duces hyper-glycsemia  even  after  division  of  the  hepatic  plexus,  and 
that  only  when  the  adrenals  are  intact  is  it  possible  to  produce  hyper- 
glycaemia  by  stimulation  of  the  nerves  of  the  liver.  Adrenine  is  there- 
fore in  some  way  necessary  to  the  activity  of  these  nerves:  possibly 
by  rendering  them  more  sensitive.  Doyen  and  Gautier  state  that  the 
effect  of  adrenine  on  the  liver  glycogen  can  be  prevented  by  atropine. 
Ergotoxine  is  also  said  to  antagonize  this  action  of  adrenine. 

If  the  liver  is  free  from  glycogen,  adrenine  injection  will  not  only 
produce  glycaemia  and  glycosuria  but  may,  even  in  fasting  animals, 
cause  glycogen  to  be  stored  in  considerable  quantity:  this  is  associated 
with  the  fact  that  the  metabolism  of  proteins  is  increased  under  the 
influence  of  adrenine,  and  the  protein  is  in  this  case  the  source  of 
the  carbohydrate  which  is  formed  (Noel  Paton).  On  the  other  hand, 
0.  Schwarz  has  found  the  liver  glycogen  to  disappear  in  rats  in  which 
the  suprarenals  have  been  removed,  although  it  can  be  restored  by 
liberal  feeding  with  glucose  and  cane  sugar  (but  not  by  laevulose  or 
starch) .  Ringer  states  that  if  the  glycogen  of  the  liver  is  got  rid  of 
by  phlorizin  adrenine  does  not  increase  the  glycosuria. 

With  the  pancreas. — Pemberton  and  Sweet  state  that  removal  of  the 
suprarenals  causes  a  flow  of  pancreatic  juice  which  is  stopped  by  in- 
jection of  adrenine,  although  under  normal  conditions  the  flow  of  pan- 
creatic juice  seems  not  to  be  affected  by  the  intravenous  injection  of 
adrenine  in  moderate  doses.  The  internal  secretion  of  this  organ  is 
however  directly  affected  by  this  hormone.  Herter  and  Wakeman 
found  that  the  mere  swabbing  of  the  exposed  pancreas  with  adrenine 
solution  provokes  an  intense  glycosuria,  comparable  with  that  produced 
by  extirpation  of  the  organ.  But  the  glycosuria  and  the  hyper- 
glycsemia  caused  by  pancreatic  extirpation  is  increased,  as  several  ob- 
servers have  found,  by  adrenine,  so  that  the  whole  of  its  effect  on  carbo- 
hydrate metabolism  is  not  exerted  through  the  pancreas  but  part  must  be 
directly  on  the  liver-cells.  We  have  in  fact  already  seen  that  adrenine  has 
a  direct  effect  on  the  glycogen  storage  of  the  liver.  But  this  is  influenced  by 
the  internal  secretion  of  the  pancreas.  Thus  Zuelzer  failed  to  get  adrenine- 
glycosuria  when  he  injected  pancreas  extract  at  the  same  time  as  the 


52  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

adrenine;  on  the  other  hand,  he  states  that  tying  the  suprarenal  veins' 
is  effectual  in  preventing  glycosuria  pancreatopriva.  These  experi- 
ments show  that  carbohydrate  metabolism  is  in  some  way  regulated  by 
the  interaction  of  the  adrenals  and  pancreas  upon  the  liver-cells. 
Graham  Lusk,  however,  from  a  study  of  the  respiratory  quotient  in  a 
glucose-fed  dog  to  which  adrenine  was  administered,  comes  to  the  con- 
clusion that  this  autacoid  does  not  act  on  carbohydrate  metabolism  by 
specifically  inhibiting  the  internal  secretion  of  the  pancreas  but  that 
its  effect  on  carbohydrate  metabolism  is  related  to  its  vasoconstrictor 
action.  The  subject  will  again  come  up  for  discussion  when  the  in- 
ternal secretion  of  the  pancreas  is  dealt  with. 

With  the  thyroid  pituitary  body. — The  mutual  relations  of  the  thy- 
roid and  suprarenals  have  already  been  discussed  under  the  former  organ. 
Those  of  the  pituitary  suprarenals  will  be  considered  when  the  functions 
of  the  pituitary  are  dealt  with. 


THE   PITUITARY   BODY  53 

LECTURE    IV. 

THE  PITUITARY  BODY,  OR  HYPOPHYSIS  CEREBRI. 

The  next  of  the  ductless  glands  to  claim  our  attention  is  the 
pituitary  body.  The  study  of  this  organ  has  sprung  into  prominence 
within  quite  recent  years.  Although  somewhat  vaguely  connected  with 
growth  phenomena  and  shown  (1887)  to  be  related  to  certain  forms  of 
abnormal  development  of  the  body  and  especially  of  the  skeleton,  it 
was  not  until  1895  that  it  was  suspected  of  having  an  active  function: 
by  most  it  was  regarded  as  a  rudimentary  structure  having  some  mor- 
phological interest  but  little  or  no  physiological  importance.  Now,  on 
the  contrary,  it  is  known  that  from  one  portion  of  the  gland  important 
autacoid  principles  can  be  extracted  which  exert  an  active  influence 
upon  some  of  the  most  essential  organs  of  the  body;  whilst  from  an- 
other portion  it  seems  probable  that  other  principles  are  furnished  to 
the  blood  which  serve  as  influential  chemical  regulators  of  nutrition  and 
growth.  Moreover,  by  most  of  those  who  have  worked  at  its  functions 
it  is  thought  to  be  essential  to  life.  In  conformity  with  this  it  is  found 
throughout  the  whole  series  of  Vertebrata  with  very  few  exceptions, 
and  these  may  ultimately  prove  only  apparent. 

The  pituitary  body  structure  is  in  man  a  small  organ  about  the  size 
of  a  hazel-nut  without  the  shell:  it  weighs  a  little  more  than  half  a 
gramme  and  lies  at  the  base  of  the  brain  in  the  sella  turcica  of  the 
spheroid  bone.  It  is  connected  with  the  floor  of  the  3rd  ventricle  by  a 
short,  hollow,  funnel-shaped  stalk — the  infundibulum.  This  stalk  is 
composed  of  nervous  tissue,  and  expands  in  the  interior  of  the  gland 
into  what  is  known  as  the  nervous  part — pars  nervosa — which  when 
examined  by  appropriate  methods  is  found  to  be  mainly  composed  of 
neuroglia  fibres  and  cells  (Herring).  In  some  animals  the  cavity  of 
the  infundibulum  with  its  lining  of  ependyma  is  prolonged  in  the 
form  of  a  blind  canal  far  into  the  pars  nervosa,  but  in  man  this  canal 
has  become  obliterated,  although  it  existed  in  the  early  embryo. 

In  front  of  and  partly  surrounding  the  pars  nervosa  the  organ  is 
formed  of  a  mass  of  epithelium  cells,  granular  in  appearance  and 
highly  vascular.  This  constitutes  the  pars  anterior  seu  glandularis. 
In  the  middle  of  the  organ  it  is  separated  from  the  pars  nervosa  by  a 
cleft  lined  by  cubical  or  flattened  epithelial  cells  and  filled  with  glairy 
fluid.  In  the  adult  human  subject  the  cleft  is  generally  found  to  be 
obliterated  or  broken  up  into  isolated  cysts  containing  a  colloid-like 
material.  The  cleft  is  all  that  remains  of  the  original  tubular  structure 
of  the  pars  glandularis,  which  in  the  early  embryo  was  formed  by  a 


54  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

pouch-like  outgrowth  of  the  buccal  ectoderm  (Rathke's  pouch)  com- 
municating at  first  with  the  cavity  of  the  mouth,  although  ultimately 
the  communication  has  become  obliterated.* 

The  pars  nervosa  does  not  actually  abut  against  the  intraglandular 
cleft,  but  is  separated  from  it  by  a  layer  of  epithelial  tissue  of  varying 
thickness,  which  was  also  originally  derived  from  the  epithelium  of 
Rathke's  pouch  but  which  differs  in  certain  respects  from  the  pars 
anterior  sen  glandularis — its  cells  being  less  granular  and  its  blood- 
vessels less  numerous.  This  portion  of  the  epithelium  is  known  as  the 
pars  intermedia  since  it  lies  between  the  pars  anterior  and  the  pars 
nervosa.  From  the  former  it  is  separated  by  the  cleft  just  described: 
from  the  pars  nervosa  there  is  no  well  defined  line  of  separation— 
indeed  cells  of  the  pars  intermedia  may  extend  for  some  distance  into 
the  pars  nervosa  between  its  neuroglial  fibres,  and  impart  to  it  an  im- 
portant functional  significance,  which  will  be  referred  to  later  in  con- 
sidering the  mode  of  secretion  of  the  pars  intermedia.  It  is  not  diffi- 
cult to  split  the  gland  across  the  middle  in  the  situation  of  the  intra- 
glandular cleft,  thus  separating  the  larger  pars  anterior  from  the  com- 
bined pars  nervosa  and  pars  intermedia.  When  such  a  separation  is 
effected  the  term  pars  posterior  or  posterior  lobe  has  been  given  to  pars 
nervosa-\-pars  intermedia,  the  pars  anterior  being  termed  in  contra- 
distinction anterior  lobe. 

Pars  anterior  sen  glandularis. — As  already  mentioned,  this  is  formed 
of  trabecular  masses  of  epithelium-like  cells  between  which  are  very 
numerous  sinus-like  blood  capillaries  lying  in  intimate  relation  to  the 
cells,  which  are  indeed  sometimes  set  closely  round  the  blood  spaces. 
So  abundant  are  the  bloodvessels  that  a  photograph  of  a  section  of  this 
part  of  the  injected  organ  appears  almost  black:  the  contrast  with  the 
pars  intermedia  and  pars  nervosa  being  well  marked.  The  pars  an- 
terior is  supplied  with  blood  by  about  eighteen  to  twenty  small  arterioles 
which  converge  towards  the  infundibulum  from  the  circle  of  Willis  and 
pass  into  it  along  the  stalk  (Dandy  and  Goetsch).  They  open  into  the 
sinusoidal  channels  which  in  this  part  take  the  place  of  capillaries; 
the  blood  from  these  passes  away  by  venules  along  the  stalk.  This 
part  of  the  pituitary  probably  constitutes  the  most  vascular  organ  in  the 
body,  even  more  so  than  the  suprarenals. 


*Traces  of  the  original  connexion  with  the  buccal  ectoderm  may,  however, 
persist  in  exceptional  cases  even  in  the  adult  (Erdheim,  Haberfeld),  as  the  so- 
called  pharyngeal  hypophysis.  Another  vestigial  structure — the  parahypophysis 
— has  been  described  by  Dandy  and  Goetsch  as  occurring  in  the  dura  mater 
lining  of  the  sella  turcica. 


THE   PITUITARY   BODY  55 

The  cells  of  the  pars  anterior  are  commonly  classified  under  two 
main  heads,  viz.,  clear,  non-staining  or  chromaphobe,  and  dark  granular, 
staining  or  chromaphil:  but  the  granular  cells  are  again  divisible  into 
oxyphil  and  basophil,  i.  e.,  those  staining  with  acid  and  basic  dy^s 
respectively,  the  basophil  cells  being  normally  however  far  the  fewer 
in  number.  It  has  been  suggested  that  these  three  types  of  cells  repre- 
sent different  stages  of  the  same  cell,  but  this  is  not  certain.  It  is  more 
probably  true  for  the  chromaphobe  cells  and  for  the  cells  with  oxyphil 
granules:  those  with  basophil  granules  appear  to  be  of  a  different 
nature.  The  cells  containing  oxyphil  granules  are  very  distinct. 
They  may  sometimes  be  seen  accumulated  around  the  blood-sinuses 
like  the  cells  of  an  ordinary  secreting  gland  around  the  lumen 
of  the  alveolus.  In  some  animals  all  the  cells  of  the  pars  anterior  are 
set  like  a  columnar  epithelium  round  the  blood-sinuses — this  is  strik- 
ingly shown  in  Elasmobranch  fishes  such  as  the  skate — while  in  the 
tortoise  columnar  cells  surround  closed  vesicles  containing  a  colloid  ma- 
terial. The  basophil  cells  are,  when  present,  mostly  found  near  the 
periphery  of  the  trabecular  masses.  In  pregnancy  peculiar  large 
finely-granular  cells  are  observed  in  considerable  number  (Erdheim  and 
Stumm)  :  these  large  cells  have  been  designated  "pregnancy  cells";  they 
appear  to  be  merely  developments  of  the  chromaphobe  cells.  Oxyphil 
cells  are  described  as  being  unusually  abundant  in  the  enlarged  gland 
of  acromegalic  subjects,  where  they  form  adenoma-like  masses  (Erd- 
heim). All  the  cells  contain  numerous  fine  fatty  globules. 

Besides  the  blood-sinuses  there  is  a  small  amount  of  reticular  con- 
nective tissue  between  the  cells.  A  few  nerves  have  been  traced  into 
the  pars  anterior  from  the  pars  nervosa. 

Under  certain  circumstances  in  man  or  mammals,  and  especially  in 
cases  of  thyroid  absence  or  insufficiency  a  product  of  secretion  of 
the  anterior  lobe  cells  which  has  the  appearance  of  "colloid"  appears 
to  accumulate  between  them,  and  in  parts  the  cells  come  to  be  arranged 
round  the  colloid  in  the  form  of  vesicles  which  are  not  very  unlike  those 
of  the  thyroid  gland.  Normally  this  appearance  is  not  observed  in  the 
pars  anterior  (Herring)  although  it  is  characteristically  seen  in  the 
pars  intermedia. 

Pars  intermedia. — As  has  been  stated,  the  pars  intermedia  although 
well  provided  with  bloodvessels  is  far  less  vascular  than  the  pars 
anterior.  At  the  circumference  of  the  intraglandular  cleft  these  two 
parts  are  continuous  into  one  another  without  a  sharp  line  of  demar- 
cation, although  it  is  easily  possible  to  distinguish  them  by  the  character 
of  their  cells.  Behind  the  intraglandular  cleft  the  pars  intermedia 


56  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

forms  a  well  marked  layer  of  varying  depth;  it  also  extends  as  a  thin 
layer  over  the  surface  of  the  pars  nervosa,  as  well  as  over  the  neck  of 
the  gland,  connecting  the  pars  nervosa  with  the  infundibulum.  The 
cells  of  the  pars  intermedia  have  not  the  coarse  oxyphil  granules  which 
are  characteristic  of  the  granular  cells  of  the  pars  anterior,  but  they 
are  finely  granular.  The  granules  are  neutrophil  and  stain  neither 
with  oxyphil  nor  with  basophil  dyes.  They  often  surround  well  denned 
vesicles  occupied  by  an  oxyphil  colloid  material:  occasionally  these 
vesicles  are  unusually  large  and  numerous,  especially  in  the  neighbor- 
hood of  the  intraglandular  cleft.  In  addition  to  these  colloid  masses 
some  of  the  cells  of  the  pars  intermedia  may  often  be  seen  in  different 
stages  of  conversion  into  globular  hyaline  bodies,  their  protoplasm  and 
nucleus  becoming  swollen;  the  latter  may  become  indistinct  and  dis- 
appear altogether.  Sometimes  the  globules  thus  produced  may  be  de- 
scribed as  granular  in  character  rather  than  hyaline.  In  both  cases 
the  cells  may  break  down,  setting  free  the  hyaline  or  granular  sub- 
stance. As  has  already  been  mentioned,  the  pars  intermedia  is  by  no 
means  everywhere  sharply  marked  off  from  the  pars  nervosa,  for  strands 
of  the  cells  of  the  pars  intermedia  may  extend  a  variable  distance  be- 
tween the  fibres  of  the  pars  nervosa.  The  hyaline  and  granular 
globules  which  have  been  derived  from  its  cells  also  pass-  into  the 
substance  of  the  pars  nervosa  and  are  seen  between  its  fibres:  they 
can  in  fact  be  traced  as  far  as  the  continuation  of  the  third  ventricle 
into  the  stalk.  This  fact  was  first  pointed  out  by  Herring,  who  con- 
cluded that  it  is  to  be  taken  as  an  indication  that  the  hyaline  and 
granular  substances  which  are  produced  by  conversion  and  breaking 
down  of  the  cells  of  the  pars  intermedia  form  the  secretion  of  this 
portion  of  the  pituitary  and  that  this  secretion  thus  passes  into  the 
cerebro-spinal  fluid.  In  confirmation  of  this  conclusion  evidence  that 
the  active  principle  of  the  posterior  lobe  of  the  pituitary  is  present 
in  cerebro-spinal  fluid  has  been  obtained  by  Gushing  and  Goetsch,  al- 
though their  conclusion  has  been  traversed  by  Carlson.  The  hyaline 
globules  are  greatly  increased  as  the  result  of  thyroidectomy  (Herring) 
and  also  after  section  of  the  infundibular  stalk  (Gushing  and  Goetsch). 

Pars  nervosa  (also  known  as  the  neuro-hypophysis  or  infundibular 
body). — This  is  formed  almost  entirely  of  neuroglia  fibres  with  neuroglia 
cells  scattered  amongst  them.  Many  of  the  fibres  arise  from  these  cells, 
others  from  the  ependyma  cells  of  the  infundibulum  and  of  its  ex- 
tension into  the  gland.  Between  the  neuroglia  fibres,  especially  in  the 
neighbourhood  of  the  stalk  but  also  in  other  situations,  is  to  be  seen 
the  hyaline  and  granular  matter  already  referred  to;  sometimes  in  the 


THE   PITUITARY    BODY  57 

form  of  swollen  cells  such  as  have  been  described  in  connexion  with 
the  pars  intermedia,  sometimes  as  amorphous  masses;  these  masses 
are  traceable,  as  already  mentioned,  to  the  infundibulum  where  they 
may  be  seen  passing  through  the  ependyma  into  the  cavity  of  the 
ventricle.  There  can  be  little  doubt  that  the  physiological  activity  of 
extracts  of  the  pars  nervosa  is  connected  with  the  presence  of  this 
substance  within  it,  since  extracts  of  ordinary  nervous  and  neuroglial 
substance  have  not  the  same  action.  Some  authors  have  described 
nerve-cells  within  the  pars  nervosa — but  according  to  Herring  these 
do  not  occur,  and  there  are  very  few  nerve  fibres.  The  pars  nervosa 
is  the  least  vascular  portion  of  the  pituitary,  its  bloodvessels  being 
comparatively  few  in  number. 

PHYSIOLOGY  OF  THE  PITUITARY — EFFECTS  OF  EXTRACTS. 

The  discovery  in  1895  by  Oliver  and  Schafer  that  extracts  of  pitui- 
tary have  a  remarkable  influence  upon  the  vascular  system,  producing 
a  great  rise  of  blood-pressure  with  contraction  of  vessels,  led  to  the 
attention  of  physiologists  being  drawn  to  this  gland,  which  had  up  to 
that  time  been  almost  entirely  neglected  by  them.  Howell  showed  that 
the  action  is  confined  to  extracts  of  the  posterior  lobe — which,  as  we 
now  know,  includes  pars  intermedia  and  pars  nervosa — and  it  has  since 
been  shown  that  it  is  yielded  by  extracts  of  either  pars  intermedia  or 
pars  nervosa  alone,  but  rather  more  distinctly  by  the  pars  nervosa  than 
by  the  pars  intermedia  (Herring).  This  is  an  additional  reason  for 
believing  that  the  material  which  produces  this  action  is  formed  by  the 
pars  intermedia  and  passes  from  this  into  and  through  the  pars  nervosa. 
The  effect  of  the  extract  upon  the  bloodvessels  is  a  direct  one  and  is 
not  due, -as  is  the  case  of  the  suprarenal  autacoid,  to  its  stimulant 
action  on  the  sympathetic  endings.  The  effect  on  the  heart  is  also 
different;  for  whereas — with  the  vagi  cut  or  paralysed — adrenine  causes 
a  marked  acceleration  of  the  heart  (sympathetic  stimulation),  the 
pituitary  autacoid  causes  a  slowing  of  the  heart's  action  along  with 
increase  in  force  of  the  individual  beats  (Howell).*  Moreover,  whilb 
adrenine  either  produces  no  action  on  the  coronary  vessels  or  according 
to  some  authors  dilates  them,  the  autacoid  of  the  pituitary  constricts 
them  as  it  does  other  systemic  arterioles;  and  the  same  is  the  case  with 
the  pulmonary  vessels.  The  pressor  or  stimulating  autacoid  also  has 
the  peculiarity  that,  as  was  first  shown  by  Howell,  the  effect  of  a 


*In  the  bird   it  augments  the  ventricular  contractions,   whereas  adrenine 
affects  the  auricles  only  in  these  animals  (Paton  and  Watson). 


58  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

second  dose  administered  a  short  interval  (30  minutes  or  less)  after 
the  first  usually  causes  no  effect ;  or,  if  any,  not  a  rise  but  a  fall  of 
blood-pressure  (Schafer  and  Vincent),  which  may  or  may  not  be  fol- 
lowed by  a  slight  rise.  Probably  therefore  there  is  present  in  the  ex- 
tract a  second  autacoid  which  is  antagonistic  to  the  first  in  its  action 
and  should  most  likely  be  classed  with  the  chalones  or  inhibitory  auta- 
coids.  On  the  heart's  action  the  repeat  dose  has  the  same  effect  as  the 
first  dose,  i.  e.,  the  beat  is  strengthened  (Biedl).  The  effect  on  the 
uterus  (see  below)  can  also  be  repeated  if  the  autacoid  is  administered 
at  short  intervals.  The  pressor  effect  and  th.e  effect  on  the  heart  pro- 
duced by  the  stimulatory  autacoid  or  autacoids  usually  lasts  a  con- 
siderable time  (a  quarter  to  half  an  hour  or  more),  varying,  however, 
with  the  dose ;  the  depressor  effect  of  the  inhibitory  autacoid  has  a 
much  shorter  period  of  activity.  The  renal  arteries  form  an  exception 
to  the  constrictor  effect  produced  by  pituitary  extract  since  they  dilate 
as  a  consequence  of  the  addition  of  the  extract  to  the  circulating 
blood:  the  dilatation  is  correlated  with  an  increase  of  secretion  of 
urine.  This  increased  secretion  may  be  in  part  brought  about  by  the 
increased  flow  of  blood  through  the  kidney  vessels,  due  to  the  cir- 
cumstance that  they  undergo  dilatation,  while  all  the  other  systemic 
arteries  are  contracting;  but  that  it  is  to  a  certain  extent  brought  about 
by  a  specific  effect  of  one  of  the  pituitary  autacoids  is  probable  from 
the  fact  that  it  may  occur  in  the  absence  of  an  arterial  change.* 

The  extract  of  pituitary  acts  upon  other  plain  muscle  tissue  besides 
that  of  the  bloodvessels.  Thus  it  powerfully  affects  the  uterus  (Dale), 
even  in  the  minute  doses,**  as  well  as  the  bladder  and  intestine  (Blair 
Bell  and  Hick)  :  it  also  produces  dilatation  of  the  pupil  of  the  excised 
eye  of  the  frog  (Cramer).  In  some  of  these  actions  it  resembles 
adrenine,  but  the  stimulating  autacoid  of  the  pituitary  is  certainly 
different  both  chemically  and  physiologically  from  that  of  the  supra- 
renal. Nor  does  it  specifically  stimulate  structures  innervated  by  the 
sympathetic  as  does  adrenine;  moreover,  neither  apocodein  nor  ergo- 
toxine  affect  the  results  obtained  with  it.  Probably  it  produces  a  direct 
effect  upon  the  contractile  substance  of  the  cells  which  it  stimulates. 


*The  effects  on  the  kidney  will  be  more  fully  dealt  with  later  on. 

**The  uterus  is  also  rendered  more  excitable  to  influences  reaching  it 
through  its  nerves.  According  to  Dale,  pituitary  extract  acts  on  plain  muscle 
more  by  increasing  its  sensitiveness  to  normal  stimuli  than  by  acting  as  a  direct 
excitant.  Thus  when  administered  in  pregnancy  before  the  commencement  of 
parturition  it  produces  no  effect:  but  its  action  during  parturition  is  well 
marked. 


THE   PITUITARY   BODY  59 

The  extracts  of  posterior  lobe  also  contain  an  autacoid  which  in- 
fluences the  secretion  of  the  mammary  gland.  If  injected  either  into 
a  vein  of  a  lactating  animal  or  intramuscularly  in  a  nursing  woman  it 
causes  a  determination  of  secretion  towards  the  nipple,  accompanied 
or  preceding  by  a  tingling  sensation  in  the  breast :  and  if  in  a  lactating 
animal  the  nipple  be  cut  or  if  a  fine  canula  be  inserted  into  one  of 
the  ducts  the  milk  flows  out  and  the  gland  becomes  emptied.* 

Lastly,  it  is  found,  as  with  adrenine,  that  the  autacoids  of  the 
posterior  lobe  of  pituitary  have  an  important  influence  upon  carbo- 
hydrate storage.  When  injected  either  into  a  vessel  or  subcutaneously 
they  produce  disappearance  of  glycogen  from  the  liver  and  they  facili- 
tate the  production  of  alimentary  glycosuria  by  lowering  the  limit  of 
assimilation  of  sugar  (Borchardt).  Whether  all  these  effects  are  pro- 
duced by  one  and  the  same  active  principle  has  not  as  yet  been  defi- 
nitely determined,  for  the  autacoids  of  the  pituitary  have  presented 
much  greater  difficulties  in  the  way  of  isolation  than  those  of  the  supra- 
renal medulla,  although  recently  more  than  one  investigator  has  suc- 
ceeded in  obtaining  crystalline  substances  which  reproduce  the  effects 
of  pituitary  extract.  Herring  has  obtained  certain  differences  of 
effect  according  as  the  extracts  are  prepared  from  the  pars  intermedia 
or  the  pars  nervosa — suggesting  that  the  autacoids  undergo  some 
alteration  in  passing  through  the  latter.  Thus  the  pars  intermedia  of 
the  ox  excites  the  uterine  muscle  and  also  the  mammary  gland  more 
than  the  plain  muscular  tissue  of  the  bloodvessels,  and  has  no  specific 
effect  on  the  kidney — nor  do  repeat  doses  show  any  immunity,  or 
hinder  extracts  of  the  pars  nervosa  from  producing  the  usual  effects  on 
blood-pressure,  kidney,  etc.,  as  well  as  its  effects  on  uterus  and  milk 
secretion. 

Subcutaneous  and  intramuscular  injections — especially  the  latter — 
produce  effects  similar  to  those  caused  by  intravenous  administration, 
although  less  rapidly.  On  the  other  hand,  buccal  administration  has 
little  or  no  effect  on  the  bloodvessels,  heart  and  plain  muscle.  This  is 
not  due  to  destruction  of  the  active  material  by  the  gastric  juice,  but 
probably  to  its  slow  rate  of  absorption  from  the  alimentary  canal. 
Addition  of  the  gland  substance  to  the  food  of  growing  animals  or  its 
administration  by  subcutaneous  injection  has  been  alleged  by  some 
observers  to  check  growth  and  delay  ossification,  but  this  statement 
appears  to  be  either  inaccurate  or  not  to  be  of  general  application.  In 
white  rats  certainly  the  growth  is  not  obviously  affected  by  the  addi- 


*These  effects  will  be  further  alluded  to  later. 


60  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

tion  of  small  amounts  of  pituitary  to  the  ordinary  food  nor  is  any 
obvious  effect  produced  upon  nitrogenous  metabolism.  In  animals  in 
which  the  gland  has  previously  been  experimentally  removed  or  in- 
jured (see  below)  Gushing  has  described  amelioration  of  the  symptoms 
as  the  result  of  adding  large  amounts  of  the  gland  substance  to  the 
food.  Pituitary  extracts  and  derivations  from  them  have  been  ad- 
ministered— with  greater  or  less  effect — in  a  variety  of  disorders,  in- 
cluding surgical  shock,  intestinal  inertia,  uterine  inertia,  amenorrhoea, 
vesical  inertia,  deficiency  of  milk  secretion,  haemoptysis,  exophthalmic 
goitre,  hay  fever,  rheumatoid  arthritis,  rickets  and  osteomalacia. 
EFFECTS  OF  REMOVAL  OR  DESTRUCTION — EXPERIMENTAL  APITUITARISM. 

A  large  number  of  experiments  have  been  made  with  the  view  of 
determining  the  nature  of  the  symptoms  which  follow  removal  of  the 
pituitary.  The  results  of  these  have  been  somewhat  conflicting  in 
character — due  in  some  measure  to  the  differences  of  method  em- 
ployed to  arrive  at  the  position  of  the  organ,  which  is  obviously  a  diffi- 
cult procedure,  deeply  as  it  is  placed  at  the  base  of  the  brain. 
Thus  while  one  set  of  operators  (e.  g.  Horsley  and  Handelsmann,  and 
Aschner),  have  preferred  to  approach  it  (in  animals)  through  the 
buccal  cavity  and  basis  cranii,  in  order  to  avoid  disturbance  of  the 
brain,  others  (e.  g.  Paulesco,  Gushing,  Biedl)  have  not  hesitated  to 
attack  it  through  a  large  aperture  in  the  side  of  the  skull,  another 
similar  aperture  being  made  on  the  opposite  side  so  as  to  enable  the 
hemispheres  to  be  pushed  over  in  order  to  obtain  a  good  view  of  the 
organ;  which  can  in  some  animals,  such  as  the  dog,  be  got  at  without 
much  difficulty  by  this  procedure.  The  former  method  has  the  dis- 
advantages (1)  that  one  is  working  at  the  bottom  of  a  deep  pit  from 
the  walls  of  which  blood  is  constantly  oozing  so  as  to  obscure  the 
operation,  and  (2)  that  it  is  impossible  to  secure  asepsis.  By  the  use 
of  the  lateral  method  these  disadvantages  are  for  the  most  part  avoided 
but  it  has  been  alleged  that  the  serious  results  which  are  described  as 
following  removal  of  the  organ  by  this  operation  are  due  to  shock 
and  paralysis  caused  by  the  unavoidable  insult  to  the  brain. 

Paulesco  was  the  first  to  state  definitely  that  complete  removal  is 
in  every  case  sooner  or  later  fatal.  This  result  was  obtained  with 
animals  from  all  classes  of  vertebrata.  Most  of  the  hypophysectomized 
mammals  died  within  two  or  three  days.  He  also  obtained  a  fatal 
result  merely  by  severing  the  stalk  connecting  the  pituitary  body  to  the 
base  of  the  brain.  Paulesco 's  statements  were  confirmed  by  Harvey 
Gushing  and  his  fellow  workers,  who  for  the  most  part  restricted 
their  experiments  to  dogs.  They  found  that  adult  animals  usually 


THE  PITUITARY   BODY  61 

succumb  after  total  deprivation  in  from  two  to  five  days,  whilst 
puppies  survive  longer  (ten  to  thirty  days)  ;  they  ascribe  this  difference 
to  the  greater  functional  adaptability  of  accessory  glandules  which  are 
probably  present  in  the  roof  of  the  pharynx  in  young  animals.  In  all 
cases  of  long  survival  a  fragment  of  the  gland,  including  some  of  the 
anterior  lobe,  was  found  post  mortem  and  they  attribute  the  survival 
to  such  a  remnant.  On  the  other  hand,  they  obtained  no  definitely 
recognisable  symptoms  by  severance  of  the  infundibular  stalk,  a  pro- 
cedure which,  as  we  have  seen,  Paulesco  alleged  to  be  fatal.  Removal 
of  part  only  of  the  anterior  lobe  is  not  at  once  fatal  but  leads  to 
certain  definite  changes  in  metabolism,  which  are  considered  by  Gush- 
ing to  be  due  to  deficient  secretion,  a  condition  to  which  he  has  given 
the  name  hypopituitarism..  Similar  results  to  those  of  Paulesco  and 
Gushing  have  been  obtained  by  Biedl  and  recently  by  Ascoli  and 
Legnani. 

The  symptoms  of  complete  removal  or  apituitarism  (cachexia  hypo- 
physeopriva)  are  described  by  Gushing  as  follows:  On  the  day  after 
the  operation  the  animal  (dog)  usually  appears  normal  with  fair 
appetite  and  no  characteristic  signs  of  loss  of  secretion.  Gradually  it 
becomes  lethargic,  refuses  food  and  responds  slowly  or  not  at  all  to 
the  voice.  Later  the  respiration  becomes  slow  and  the  pulse  both  slow 
and  feeble,  the  musculature  limp,  often  with  tremors  and  fibrillar 
twitching;  the  back  is  arched,  and  the  temperature  subnormal;  finally, 
often  within  48  hours,  the  animal  becomes  comatose  and  dies  in  this 
condition.  According  to  Gushing  immediate  replantation  of  the  removed 
gland  in  some  other  structure  causes  an  abatement  of  the  symptoms 
and  prolongs  life,  but  whether  indefinitely  or  not  is  uncertain  and 
would  doubtless  depend  upon  whether  the  graft  underwent  subsequent 
degeneration.  In  Gushing 's  later  experiments  extirpation  of  the  gland 
seems  to  have  been  less  certainly  fatal  or  longer  delayed,  the  animals 
exhibiting  the  symptoms  rather  of  hypo-  than  of  a-pituitarism.  This 
may  be  due  to  small  portions  of  the  gland  having  been  left  be- 
hind or  to  the  employment  of  younger  animals  or  to  the  vicarious 
activity  of  some  other  organ  or  organs.  The  fact  is  interesting  because 
Aschner,  who  has  performed  a  large  number  of  extirpations  mainly  by 
the  inferior  operation  (through  the  base  of  the  skull),  has  not  found 
the  gland  to  be  essential  to  life — or  at  least  has  obtained  very  con- 
siderable prolongation  of  life  after  its  entire  removal.  It  must,  however, 
be  regarded  as  doubtful  if  it  is  possible  to  effect  complete  removal  by 
this  operation.  Aschner  himself,  who  admits  the  difficulty,  regards  the 
small  residue  as  unimportant.  In  all  his  cases  symptoms  of  hypopituitar- 
ism showed  themselves.  His  animals,  if  young,  remained  small:  their 


<>*  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

milk  teeth  were  retained  and  also  their  lanugo  hair:  their  epiphyses  did 
not  ankylose.  The  thyroid  was  enlarged,  the  thymus  persistent,  and  the 
cortex  of  the  suprarenal  thickened.  In  the  adult  the  chief  effect  of  the 
removal  was  the  putting  on  of  fat.  In  pregnant  animals  Aschner  found 
removal  of  the  pituitary  to  be  always  followed  by  abortion. 

The  experiments  of  others  have  yielded  different  results.  Thus 
Horsley  and  Handelsmann,  who  performed  complete  extirpat;on  in  a 
number  of  animals  chiefly  by  the  operation  through  the  base  of  the  skull, 
state  that  although  a  large  proportion  of  their  cases  died  within  forty- 
eight  hours  they  consider  this  was  due  to  causes  incidental  to  the  opera- 
tion (shock,  haemorrhage,  infection).  Those  that  survived  showed  none 
of  the  symptoms  above  described  as  characteristic  of  apituitarism.  But 
in  view  of  the  results  of  clinical  observations  on  the  effects  of  destructive 
disease  of  the  pituitary  it  must  be  regarded  as  doubtful  whether  the 
removal  of  the  gland  has  been  as  complete  in  these  cases  as  in  those 
described  by  Paulesco  and  Gushing,  the  operative  method  employed  by 
whom  seems  on  the  whole  less  open  to  objection  than  that  in  which  the 
gland  is  reached  through  the  basi-spheroid. 

Experimental  hypopituitarism. — The  results  of  lesions  which  involve 
only  partial  removal  or  destruction  are  in  some  respects  even  more  inter- 
esting than  those  in  which  the  extirpation  is  complete  and  the  symptoms 
more  acute.  The  most  striking  effects  are  obtained  in  young,  growing 
animals.  Retardation  of  growth  after  hypophysectomy  has  been  de- 
scribed by  various  authors  and  that  this  is  a  characteristic  of  diminished 
amount  of  pituitary  substance  and  concomitant  diminished  secretion  of 
autacoids  by  the  gland  has  been  established  by  the  experiments  of  Gush- 
ing and  of  Biedl.  The  work  of  Aschner,  which  has  just  been  alluded  to, 
also  obviously  has  an  important  bearing  upon  this  point,  although  Asch- 
ner himself  believes  that  in  most  of  his  operations  the  removal  was  com- 
plete and  that  the  condition  was  one  of  apituitarism.  The  retardation  in 
development  shows  itself  in  a  general  diminution  in  size,  in  imperfection 
in  the  ossification  process,  and  in  the  sexual  organs,  which  long  retain 
their  infantile  condition.  At  the  same  time  there  is  a  marked  tendency 
to  fat  formation,  so  that  the  actual  weight  of  the  operated  animals  may 
exceed  that  of  the  controls.  Even  in  adult  animals  a  tendency  to  obesity 
is  a  characteristic  feature  after  partial  hypophysectomy.  Accompanying 
this  tendency  and  possibly  acting  as  a  causative  agent,  is  a  high  tolerance 
for  sugars,  the  limit  of  alimentary  glycosuria  being  markedly  increased. 
This  is  the  directly  contrary  effect  to  that  produced  by  injection  of  pos- 
terior lobe  extract  and  is  doubtless  the  result  of  deficiency  of  posterior 
lobe  secretion  which  in  Gushing 's  opinion  "is  essential  to  effective  carbo- 


THE  PITUITARY   BODY  63 

hydrate  metabolism."  It  was  found  by  Gushing  (in  conjunction  with 
Goetsch  and  Jacobson)  that  immediately  after  the  operation  of  partial 
hypophysectomy  a  temporary  glycosuria  would  at  first  usually  ensue. 
This  result  is  perhaps  due  to  a  dislodgement  of  accumulated  secretion 
and  irritation  due  to  the  injury.  The  effect,  however,  soon  passes  off 
and  is  followed  by  the  permanent  condition  of  increased  tolerance  for 
sugar.  Animals  which  have  acquired  this  tolerance  will  suffer  loss  of 
the  pancreas  without  becoming  diabetic.  Injury  to  the  posterior  lobe  or 
even  its  manipulation  is,  probably  for  the  same  reason  (release  of  accumu- 
lated secretion  and  possibly  temporary  irritation  due  to  the  injury),  often 
immediately  followed  by  marked  glycosuria  and  also  by  polyuria 
(Schafer),  which  may  persist  long  after  the  glycosuria  has  disappeared 
or  may  be  present  from  the  first  without  glycosuria  (diabetes  insipidus). 
In  one  case  of  such  injury  to  the  pituitary  in  a  dog  operated  upon  by 
Schafer  the  amount  of  urine  rose  from  40  c.  c.  per  diem  to  230  c.  c.,  and 
during  the  following  19  days  remained  at  an  average  of  119  c.  c.  In 
another  it  rose  from  110  c.  c.,  the  average  of  11  normal  days,  to  182  c.  c., 
the  average  of  the  11  days  immediately  succeeding  the  operation.  It  was, 
however,  much  higher  than  this  on  the  3d,  4th  and  5th  days,  averaging  266 
c.  c.  Mere  exposure  of  the  pituitary  was  found  to  have  no  such  effects. 
A  case  in  man  has  been  recorded  by  Simmonds  in  which  there  was  a 
malignant  tumour  of  the  pars  nervosa  extending  to  the  pars  intermedia, 
with  marked  diabetes  insipidus  (10  to  19  litres  of  urine  per  diem).  This 
is  probably  a  case  of  the  cells  of  such  a  tumour  assuming  the  functions  of 
the  tissues  they  are  invading  (see  footnote,  page  14).  It  has  been  found 
by  Gushing  that  stimulation  of  the  cervical  sympathetic  or  of  its  superior 
ganglion  causes  diuresis;  he  considers  this  is  brought  about  by  provok- 
ing the  secretion  of  the  posterior' lobe.  Stimulation  of  the  superior 
cervical  ganglion  produces  no  effect  if  the  pituitary  be  first  removed. 
Therefore,  it  is  concluded  that  secreting  nerves  pass  through  this  ganglion 
to  the  pituitary.  Gushing  also  states  that  excision  of  the  posterior  lobe  or 
separation  of  the  stalk  is  sometimes  followed  by  prolonged  polyuria :  this 
may  be  caused  by  irritation  of  portions  of  pars  intermedia  which  remain. 
According  to  Weed,  Gushing  and  Jacobson,  puncture  of  the  pituitary 
gives  as  definite  results  regarding  glycosuria  as  Bernard's  puncture  of 
the  4th  ventricle.  In  both  cases  there  must  be  " available"  glycogen 
present,  i.  e.  glycogen  resulting  from  recent  ingestion  of  carbohydrates. 
Both  this  and  Bernard's  puncture  are  ineffective  after  section  of  the  cord 
at  the  4th  thoracic  level.  Mental  dullness  has  also  been  noticed  in  par- 
tially hypophysectomized  animals.  Most  of  the  above  symptoms  have  been 
recognized  in  the  human  subject  in  affections  involving  the  pituitary  and 
presumably  also  result  from  hypopituitarism. 


64  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

EFFECTS  OF  GRAFTING  AND  FEEDING  WITH  PITUITARY. 

Experimental  hyperpituitarism. — Many  attempts  have  been  made  to 
increase  the  internal  secretion  of  the  pituitary — especially  of  the  pars 
anterior — by  grafting  the  organ  or  portions  of  the  organ  from  an  animal 
of  the  same  species  into  various  parts  of  the  body — but  these  have  always 
so  far  resulted  in  failure,  the  graft  disappearing,  or  at  any  rate  under- 
going degeneration,  in  the  course  of  a  few  days.  In  white  rats,  rabbits 
and  guineapigs  I  have  repeatedly  implanted  the  organ  as  a  whole  or  in 
small  pieces  under  the  skin  of  the  groin,  in  the  peritoneal  cavity,  in  the 
kidney  substance,  in  the  spleen  and  in  the  substance  of  the  brain,  but 
always  with  no  result  or  with  only  a  temporary  effect  upon  the  amount  of 
urine  secreted,  which  has  obviously  been  due  to  the  autacoid  of  the  pos- 
terior lobe.  Only  after  extirpation  of  the  animal's  own  gland  did  Gush- 
ing and  his  fellow  workers  succeed  in  occasionally  getting  a  graft  to  take 
(for  at  least  a  month).  A.  Exner  seems  also  to  have  obtained  something 
like  a  positive  result  in  rats  without  previous  removal  of  the  animal's  own 
gland,  for  he  states  that  he  was  able  to  observe  a  temporary  increase  of 
growth  of  animals  in  which  he  implanted  an  extra  pituitary  as  compared 
with  controls.  Other  methods  which  might  be  expected  to  produce  hyper- 
pituitarism consist  (1)  in  the  addition  of  pituitary  substance  to  the  food, 
(2)  in  the  subcutaneous  injection  of  extracts  at  regular  intervals  dur- 
ing a  prolonged  period  of  time.  The  second  method  has  been  stated  by 
some  observers  to  produce  a  retardation  of  growth  of  the  skeleton  and  of 
the  body  generally — a  result  exactly  the  contrary  to  what  would  be  ex- 
pected if — as  there  seems  no  reason  to  doubt — the  symptoms  of  acrome- 
galy,  presently  to  be  described,  are  due  to  hypertrophy  of  the  gland, 
especially  of  the  anterior  part.  A  series  of  experiments  by  the  first 
method  which  were  carried  out  by  me  upon  white  rats  and  extended  over 
several  months  showed  no  constant  effect  in  facilitating  the  growth  of 
young  animals — although  there  was  no  sign  of  retardation :  the  material 
appears,  therefore,  to  be  inert  when  thus  administered.  This  absence  of 
result  may  be  due  to  chemical  changes  effected  in  the  active  principles  of 
the  anterior  lobe  by  the  digestive  juices,  or  it  may  be  that  the  material  of 
the  secretion  of  the  cells  of  the  pars  anterior  is  inert  whilst  within  the 
cells,  and  only  becomes  active  at  the  moment  of  discharge  into  the  blood- 
stream. 

CLINICAL  EVIDENCE. 

Clinical  symptoms  due  to  overgrowth  or  deficiency  of  pituitary. — The 
clinical  symptoms  due.  respectively  to  overgrowth  and  to  deficiency  are 
characteristic.  Although  these  symptoms  have  long  been  recognized, 


THE   PITUITARY   BODY  65 

some  of  them  have  only  comparatively  recently  been  properly  inter- 
preted as  the  result  of  pituitary  dystrophy.  This  advance  in  knowledge 
has  mainly  been  due  to  the  experiments  on  animals  to  which  allusion  has 
already  been  made.  The  literature  of  the  subject  is  rapidly  becoming 
enormous.  Every  day  a  larger  number  of  cases  are  recognized  to  be  re- 
lated to  some  perversion  of  function  of  this  organ,  and  affections  which 
were  previously  obscure  are  becoming  elucidated.  A  large  number  of 
cases  in  which  the  pituitary  probably  plays  a  causative  part  have  been  de- 
scribed by  Harvey  Gushing  in  his  book,  "The  Pituitary  Body  and  Its 
Disorders,"  1910,  a  work  which  must  in  future  form  the  starting  point 
for  the  stu^y  of  this  organ  in  its  clinical  aspects. 

The  course  of  many  cases  of  disorder  of  the  pituitary  body  (termed 
by  Gushing  dyspituitarism)  is  as  follows:  Starting  with  enlargement  of 
the  gland,  they  are  heralded  by  symptoms  of  excessive  function  (hyper- 
pituitarism) .  After  a  variable  time — which  may  be  greatly  prolonged — 
degenerative  changes  in  the  enlarged  organ  supervene  and  there  results 
from  this  a  gradual  diminution  (hypopituitarism) ,  or  even  eventually 
an  entire  loss  of  function  (apituitarism) .  The  primary  enlargement  is 
usually  first  recognized  by  diminution  of  the  visual  field,  caused  by  the 
pressure  of  the  enlarging  gland  upon  the  optic  chiasma ;  hence  these  affec- 
tions generally  come  first  under  the  notice  of  the  ophthalmic  surgeon. 
The  loss  of  vision  may  not  be  produced  by  actual  destruction  of  nerve 
fibres,  for  it  has  frequently  been  noticed  that  after  operation  for  removal 
of  the  tumour  or  alleviation  of  the  pressure  produced  by  it  the  patient's 
vision  is  speedily  restored.  Accompanying  the  visual  symptoms  or  pre- 
ceding them  certain  other  signs  are  developed  which  point  to  the  advent 
of  a  peculiar  affection  which  is  known  as  acromegaly ,  and,  in  one  of  its 
forms,  as  gigantism*.  The  affection  to  which  the  name*  acromegaly  was 
given  by  Marie  (1886)  had  been  already  described  by  others  and  its 
association  with  enlargement  of  the  pituitary  body  had  been  recognized. 
But  it  is  to  Marie — associated  later  with  Marinesco — that  we  owe  the 
first  complete  account  of  the  syndrome  in  question.  The  name  which  he 
bestowed  upon  it  expresses  its  most  prominent  sign,  viz:  "hyper- 
trophie  singuliere  non-congenitale  des  extremites  superieures,  in- 
ferieures  et  cephalique" — a  marked  non-congenital  enlargement  of  the 
limbs  and  head.  The  hands,  feet  and  face  are  especially  hypertrophied 
and  X-ray  photographs  show  a  typical  mushrooming  of  the  ungual 
phalanges.  But  the  enlargement  is  not  confined  to  the  bones  of  the 
extremities;  it  affects  the  whole  skeleton,  which  becomes  thickened  and 
hypertrophied.  There  is  usually  a  corresponding  muscular  development ; 


*'a.Kpov,  extremity;  ptyas,  large. 


66  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

the  subject  becoming  abnormally  strong.  The  affection  does  not  super- 
vene until  adult  life  is  attained,  i.  e.  until  the  epiphysial  cartilages  are 
ossified,  so  that  the  long  bones  do  not  grow  in  length  and  the  stature  is 
but  little  affected,  any  increase  of  stature  that  is  produced  by  increase 
of  the  vertebral  column  being  usually  more  than  compensated  for  by  a 
kyphosis,  which  supervenes  after  the  disease  has  made  some  progress. 
But  if  the  hyperpituitarism  commences  whilst  the  cartilages  are  still  unos- 
sified  there  is  a  considerable  growth  in  length  of  the  long  bones  so  that 
the  patient  attains  an  unusual  height.  The  affection  is  then  known  as 
gigantism,  but  is  of  essentially  the  same  nature  and  origin  as  acromegaly 
(Tamburini,  Woods-Hutchinson,  Lannois  and  Roy).* 

In  practically  all  cases  of  both  acromegaly  and  gigantism  there  is 
enlargement  of  the  pituitary.  This  increase  in  bulk  often  takes  the  form 
of  a  considerable  tumour,  which  can  usually  be  detected  during  life  in 
skiagrams  of  the  skull,  the  sella  turcica  showing  a  well-marked  enlarge- 
ment. The  tumour  is  usually  found  to  affect  mainly  or  entirely  the 
anterior  lobe,  and  its  character  is — at  least  at  first — of  the  nature  of  a 
hyperplasia  or  adenoma  (Benda),  although  in  later  stages  degenerative 
or  malignant  changes  may  establish  themselves.  The  tumour,  if  large,  is, 
as  already  mentioned,  liable  to  affect  vision  and  to  produce  headache  and 
other  symptoms  of  intracranial  pressure. 

In  addition  to  the  skeletal  changes  others  occur.  The  integument  be- 
comes thickened ;  there  is  increased  activity  of  the  skin  glands  and  a  ten- 
dency to  an  abnormal  increase  in  the  growth  of  the  hair  over  the  body 
(hypertrichosis) .  Diminution  of  sexual  activity  often  supervenes  early 
in  the  disease,  although  it  may  be  preceded  by  the  opposite  condition. 
Th.ere  is  often  glycosuria**  or  simple  polyuria :  when  present  these  con- 
ditions are  probably  associated  with  hypertrophy  of  the  posterior  rather 
than  of  the  anterior  lobe.  As  the  case  advances  they  may  be  replaced  by 
high  degrees  of  sugar  tolerance,  due  to  a  subsequent  hypoplasia  or  degen- 
eration of  this  lobe.  It  is  interesting  to  note  that  in  pregnancy  also — in 
which  the  pituitary  is  found  to  undergo  enlargement — glycosuria  not  in- 
frequently occurs. 

Marie  and  Marinesco  were  originally  inclined  to  the  view  that 
acromegaly  is  due  to  destructive  disease  of  the  gland,  since  in  many 
cases  it  is  found  post  mortem  that  the  tumour  is  of  malignant  character 


*There  is  little  question  that  most  instances  of  gigantism  are  pathological, 
and  it  is  well  known  that  "giants"  are  comparatively  short-lived. 

**According  to  Andre  Levi  glycosuria  occurs  in  30-50%  of  cases  of  acro- 
megaly. 


THE   PITUITARY   BODY  67 

and  that  the  substance  of  the  gland  has  been  destroyed.**  It  was  this 
idea  which  led  to  the  carrying  out  by  various  investigators  of  experi- 
ments for  the  removal  or  destruction  of  the  organ  in  animals,  in  order 
to  produce,  if  possible,  a  similar  syndrome.  But  so  far  from  producing 
increased  growth,  this  operation  led  to  the  opposite  result,  the  develop- 
ment of  the  skeleton  and  body  generally  being  retarded  and  restrained. 
It  is  now  recognized  that  the  tumours  of  the  gland  which  are  associated 
with  acromegaly  are  in  the  first  instance  of  a  glandular  (adenomatous) 
type ;  although  they  may  later  become  of  a  malignant  or  of  a  cystic  na- 
ture and  lead  to  the  destruction  of  the  glandular  tissue.  It  is,  therefore, 
held  by  most  authorities  that  the  characteristic  symptoms  of  acromegaly 
are  originally  due  to  hyperpituitarism,  i.  e.  to  increased  function 
(although  it  may  be  that  there  is  also  some  degree  of  perversion  of 
function) .  In  later  stages  effects  of  destruction  may  undoubtedly  become 
apparent  and  supersede  the  symptoms  of  hypertrophy.*  Since  no  one  has 
yet  succeeded  in  producing  the  effects  of  hyperpituitarism  experiment- 
ally, either  by  operation  or  by  feeding  with  the  gland,  the  evidence  of 
their  causation  by  excess  of  internal  secretion  is  mainly  founded  on  the 
clinical  features  of  cases  of  enlargement  of  the  organ. 

Other  clinical  cases  appear  to  be  explicable  only  by  supposing  that 
there  exists  glandular  insufficiency  (hypopituitarism).  There  is,  as  we 
have  seen,  evidence  derived  from  the  results  of  partial  destruction  in  ani- 
mals as  to  the  symptoms  which  may  result  from  deficiency  of  secretion 
(p.  7).  When  similar  symptoms  occur  in  man  it  is  therefore  natural 
to  conclude  that  they  have  the  same  cause,  viz. :  pituitary  insufficiency ; 
and  in  some  cases  it  has  been  possible  to  obtain  evidence  (by  skiagrams 
or  post  mortem  examination)  of  a  deficiency  in  size  of  the  organ. 

It  must  be  stated  that  by  no  means  every  case  of  tumour  of  the 
pituitary  is  accompanied  by  the  symptoms  of  acromegaly.  For  the  dis- 
ease may  from  the  first  be  destructive  and  at  once  tend  to  the  opposite 
condition,  viz. :  hypopituitarism,  with  its  own  characteristic  features. 
This  is  probably  what  happens  in  the  syndrome  described  by  Frb'hlich 
(1901)  and  termed  by  Bartels  dystrophia  adiposogenitalis.  The  symp- 
toms of  this  affection  closely  simulate  those  of  animals  which  have  under- 
gone partial  or  complete  removal  of  the  gland.  One  often  quoted  case 


**Marie  appears  more  recently  to  have  modified  his  views;  inclining  on  the 
whole  to  the  belief  that  it  is  a  perversion  and  not  a  suppression  of  the  secretion 
which  leads  to  the  abnormal  growth. 

*Sometimes  the  tumour  of  the  gland  is  from  the  first  malignant,  but  it  is 
stated  that  even  then  many  of  the  cells  tend  to  resemble  those  of  the  normal 
gland  (malignant  adenoma)  and  symptoms  of  acromegaly  are  still  produced. 


68  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

in  which  such  symptoms  made  their  appearance  was  described  by  Made- 
lung  in  1904  in  a  girl  of  nine  years  of  age  whose  pituitary  was  destroyed 
by  a  bullet  which  lodged  in  the  sella  turcica. 

The  symptoms  which  are  believed  to  be  due  to  pituitary  insuffi- 
ciency, as  might  be  supposed,  are  the  reverse  of  those  ascribed  to  hyper- 
pituitarism.  If  the  affection  commence  before  adolescence  the  stature 
(instead  of  becoming  gigantic  as  in  hyperpituitarism)  remains  small. 
This  is  generally  associated  with  marked  adiposity,  so  that  the  weight  of 
the  body  may  be  large  relatively  to  the  height.  Sexual  development  is 
delayed  and  may  remain  largely  in  abeyance,  producing  a  more  or  less 
permanent  condition  of  sexual  infantilism.  In  the  .female  the  menses  are 
irregular  or  absent  and  in  both  sexes  there  is  deficient  development  of 
secondary  sexual  characters  such  as  the  hair  on  the  face  (in  the  male) 
and  over  the  pubes  in  both  sexes.  Such  hair  as  occurs  in  this  last  men- 
tioned situation  in  the  male  does  not  extend  to  the  umbilicus  as  usual 
in  that  sex,  but  assumes  the  disposition  characteristic  of  the  female,  be- 
ing limited  to  the  mons  veneris.  On  the  other  hand,  the  hair  of  the  head 
is  generally  abundant.  Nor  is  the  character  of  the  trichosis  the  only  sign 
of  feminism  in  subjects  affected  by  hypopituitarism.  They  show  also  a 
broad  pelvis,  with  a  certain  amount  of  genu  valgum,  small  extremities 
with  tapering  fingers,  and  occasionally  well-marked  mammary  develop- 
ment. Skiagrams  of  the  long  bones  generally  exhibit  persistent  epi- 
physial  lines.  The  skin  is  smooth  and  delicate  and  free  from  moisture. 
The  nails  are  small  and  thin  and  the  crescents  at  their  base  are  absent. 

The  tendency  to  adiposity  is  attributable  by  Gushing  to  deficiency  of 
posterior  lobe  secretion.  This  deficiency  is  associated  with  unusual  toler- 
ance to  sugar  and  an  excessive  assimilative  power  for  carbohydrates, 
which  become  transformed  into  fat  and  thus  produce  adiposity.  These 
cases  are,  however,  sometimes  associated  with  glycosuria,  although  more 
often  there  is  polyuria  without  sugar  (diabetes  insipidus). 

The  hypopituitarism  may  occur  along  with  simple  atrophy  of  the 
gland,  as  appears  to  be  the  case  in  the  instance  of  infantilism  described 
by  Dr.  Byrom  Bramwell  (Clinical  Studies  VI,  1908),  in  which  the  skia- 
gram shows  a  small  sella  turcica.  Or  it  may  be  caused  in  other  ways, 
e.  g.  by  the  formation  of  a  cyst  partially  destroying  the  gland,  or  as  the 
result  of  pressure  from  a  neighboring  tumour. 

A  subnormal  body-temperature  is  generally  associated  with  the 
above  symptoms  as  well  as  low  arterial  tension  and  a  slow  pulse;  there 
is  also  usually  drowsiness  and  torpidity.*  The  excretion  of  carbon  diox- 


*Most  of  these  symptoms  are,  as  pointed  out  by  Gushing,  somewhat  similar 
to  those  exhibited  by  hibernating  animals. 


THE   PITUITARY   BODY  69 

ide  was  found  by  Benedict  and  Romans  to  be  markedly  decreased.  Some- 
times evidences  of  psychic  derangements  and  occasionally  a  tendency  to 
epilepsy  have  been  described. 

When  the  hypopituitarism  comes  on  after  adolescence  certain  of  the 
above  symptoms  will  be  missed,  but  the  lowered  temperature,  the  toler- 
ance to  sugar  and  the  supervention  of  excessive  adiposity  are  generally 
present,  as  well  as  the  dryness  of  the  skin  and  loss  of  hair,  and  a  ten- 
dency in  the  male  to  adopt  the  feminine  type  of  trichosis,  even  in  cases 
where  the  male  type  has  already  been  established.  According  to  Gush- 
ing, "pigmentation  of  the  skin  is  a  conspicuous  feature  of  many  of  the 
adult  states,  and  as  it  is  apt  to  be  associated  with  asthenia  or  a  low 
blood-pressure  it  is  natural  to  ascribe  it  to  an  associated  adrenal  insuf- 
ficiency, though  it  hardly  reaches  the  degree  of  bronzing  seen  in  some 
of  the  Addisonian  examples  of  adrenal  tuberculosis." 

As  has  already  been  stated,  the  history  of  some  cases  of  affections  of 
the  pituitary  shows  symptoms  characterizing  hypopituitarism  following 
those  characteristic  of  hyperpituitarism,  although  of  course  little  or  no 
retrogression  in  the  growth  of  the  skeleton  and  body  can  generally  be 
expected.  Thus  the  occurrence  of  hyperplasia  and  hyperpituitarism  dur- 
ing adolescence  leading  to  a  general  overgrowth  of  the  body  and  unusual 
growth  of  hair,  and  sometimes  accompanied  by  sexual  precocity,  may  be 
followed  by  glandular  hypoplasia  and  diminution  of  the  sexual  instinct, 
with  or  without  impotence,  as  well  as  by  excessive  adiposity,  and  the 
assumption  by  the  male  of  some  of  the  feminine  characteristics  which 
have  been  above  described  as  associated  with  hypopituitarism.  This  alter- 
ation in  the  signs  of  disease  complicates  th,e  clinical  features  of  many 
cases;  the  complications  can  only  be  unravelled  by  a  careful  study  of 
the  history  of  each  case. 

In  many  instances  where  the  affection  begins  with  hyperplasia  of 
the  gland  and  subsequent  changes  produce  destruction  or  degeneration 
of  the  enlarged  organ,  leading  eventually  to  apituitarism,  these  changes 
may  occupy  years  in  their  development,  but  the  patient  ultimately  loses 
strength  and  gradually  wastes.  Under  such  circumstances  death  results 
from  a  state  which  is  probably  analogous  to  the  cachexia  hypophyseopriva 
described  by  Paulesco,  Gushing  and  Biedl  in  the  animals  operated  on  by 
them.  It  seems  likely  that  this  is  the  usual  course  of  the  disease  known 
as  acromegaly,  of  which  it  is  still  uncertain  regarding  some  of  the  symp- 
toms whether  they  are  to  be  regarded  as  associated  with  hyper-  or  hypo- 
pituitarism. That  the  acromegalic  skeletal  growth  is  produced  by  hyper- 
trophy and  oversecretion  (or  perverted  secretion)  of  the  anterior  lobe  is 
highly  probable,  both  as  the  result  of  partial  extirpation  in  animals  and 


70  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

from  the  effect  of  operative  removal  of  pituitary  tumours  in  man.  One 
case  in  particular  is  described  by  Hochenegg  (1908)  as  having  shown 
within  a  few  days  of  operation  for  removal  remarkable  amelioration  of 
the  symptoms,  with  gradual  diminution  in  size  of  the  enlarged  extremi- 
ties, and  eventually  complete  cure.  The  thyroid  gland  both  in  this  and 
in  another  instance  which  was  also  successfully  operated  upon  by  the 
same  surgeon  became  permanently  enlarged.  In  both  the  tumour  was 
a  malignant  adenoma.  In  other  cases  operated  on  by  Hochenegg,  Gush- 
ing and  others,  in  some  of  which  an  enlarged  anterior  lobe  only  was  re- 
moved, although  the  results  have  for  the  most  part  been  less  striking 
than  in  the  above  examples,  the  retrogression  of  the  disease  symptoms 
resulting  from  the  partial  extirpation  of  the  tumour  and  especially  of  its 
anterior  lobe  was  distinct  and  apparently  permanent. 

We  are  therefore  doubtless  warranted  in  believing  that  the  enlarge- 
ment of  the  skeleton  and  the  other  signs  which  are  characteristic  of 
acromegaly  are  due  to  hypertrophy  of  the  anterior  lobe  of  the  pituitary, 
whilst  hypertrophy  of  the  posterior  lobe  produces  totally  different  effects 
on  metabolism.  Further,  the  symptoms  due  to  hypopituitarism  vary 
according  as  the  anterior  or  the  posterior  lobe  of  the  gland  is  mainly 
affected.  In  the  former  case  the  chief  effect  seems  to  be  upon  the  stat- 
ure. When,  however,  it  is  the  posterior  lobe  which  is  affected,  a  tendency 
to  fat  formation  and  to  deficient  sexual  development  are  usually  mani- 
fested, without  being  necessarily  accompanied  by  diminution  in  stature ; 
indeed,  they  may  be  associated  with  increased  growth  of  the  body, 
although  not  especially  affecting  the  skeleton,  and  a  characteristic  infan- 
tile condition  is  retained.  Karely  these  symptoms  of  deficiency  of  pos- 
terior lobe  occur  along  with  acromegalic  symptoms,  and  are  then  asso- 
ciated with  concomitant  enlargement  of  anterior  lobe.  That  the  adiposity 
is  related  to  a  deficiency  of  the  posterior  lobe  is  further  indicated  by  the 
fact,  according  to  Strada,  that  it  is  never  accompanied  by  glycosuria  or 
polyuria,  symptoms  which  are  almost  certainly  the  result  of  increase  of 
activity  of  that  lobe. 

In  connexion  with  the  influence  of  the  anterior  part  of  the  organ  on 
growth,  cases  of  dwarfs  have  been  described  in  which  the  pituitary  has 
been  noticeably  small  and  atrophied;  although  on  the  other  hand  others 
have  been  recorded  in  which  the  contrary  condition  has  been  found. 
The  supposition  that  in  these  latter  cases  the  enlargement  is  not  a  true 
glandular  growth  as  in  acromegaly,  but  of  an  abnormal  or  destructive 
character,  is  attractive.  We  must,  however,  be  careful  not  to  adopt  it 
too  readily  simply  because  it  seems  to  fit  in  with  what  is  known  of  the 
effect  of  overgrowth  of  the  organ  in  producing  giants  and  acromegalics. 


THE  PITUITARY   BODY  71 

But  in  more  than  one  such,  case  of  a  dwarf  with  enlargement  of  pituitary 
the  tumour  has  been  found  to  be  really  outside  the  gland  and  to  exercise 
compression  upon  it.  It  must  be  remembered  also  that  increased  activity 
of  the  natural  function  of  an  organ  may  not  necessarily  accompany  in- 
crease in  volume:  this  is  exemplified  in  cases  of  endemic  goitre.  There 
is  on  the  whole,  therefore,  reason  to  believe  that  a  dwarfish  habit  of  body 
is  associated  with  diminution  either  in  size  or  in  activity  of  the  anterior 
lobe  of  the  pituitary.  These  changes  may  commence  in  infancy  or  even 
in  the  foetus. 

Assuming  that  the  two  parts  of  the  gland  have  different  functions — the 
anterior  furnishing  autacoids  which  govern  the  growth  of  the  skeleton  and 
body  generally,  the  posterior,  autacoids  which  affect  carbohydrate  metabolism, 
fat  formation,  and  the  development  of  the  sex  glands  as  well  as  stimulate  invol- 
tary  muscle,  and  certain  secretions,  especially  those  of  the  kidneys  and  mam- 
mary gland,  it  is  obvious  that  as  the  result  of  increase  or  diminution  of  vol- 
ume and  function  of  either  part  the  clinical  symptoms  manifested  in  affections 
in  which  this  organ  is  involved  may  take  very  different  characters.  Thus  we 
may  have  symptoms  resulting  from  (1)  (2)  general  hyperpituitarism  or  hypopit- 
uitarism  involving  both  anterior  and  posterior  lobes,  (3)  (4)  anterior  hyper- 
pituitarism or  hypopituitarism  involving  the  anteroir  lobe  alone,  (5)  (6)  pos- 
terior hyper-  or  hypopituitarism  involving  the  posterior  lobe  alone,  (7)  anterior 
hyperpituitarism  combined  with  posterior  hypopituitarism,  and  (8)  anterior 
hypopituitarism  combined  with  posterior  hyperpituitarism.  In  all  of  these 
eight  conditions  the  clinical  appearances  would  be  different. 

RELATIONS  OF  THE  PITUITARY  TO  OTHER  GLANDULAR  ORGANS. 

The  relationship  of  the  pituitary  to  other  glands  is  more  extensive 
than  that  of  any  of  the  other  internally  secreting  organs.  Ascoli  and 
Legnani  found,  in  dogs  which  survived  for  a  sufficient  time  the  opera- 
tion of  removal  of  pituitary,  a  diminution  in  volume  of  the  spleen,  with 
disappearance  of  the  Malphigian  corpuscles,  precocious  retrogression  of 
the  thymus,  enlargement  of  the  thyroid  due  to  accumulation  of  colloid 
within  its  follicles  similar  to  that  seen  in  endemic  goitre,  and  an  in- 
crease of  lipoids  in  the  cells  of  the  cortex  of  the  suprarenals. 

Relative  to  the  adrenals. — That  there  is  some  relationship  between 
the  autacoids  of  the  pituitary  and  of  the  medulla  of  the  suprarenal  cap- 
sule would  appear  from  the  fact  that  that  of  the  posterior  lobe  of  the 
pituitary  and  that  of  the  suprarenal  medulla  mutually  facilitate  one 
another's  action,  especially  upon  the  bloodvessels.  Thus  an  immediately 
prior  injection  of  even  a  small  dose  of  adrenine  will  increase  the  effect  of 
a  dose  of  pituitarine  and  vice  versa. 

There  is  also  some  evidence  to  show  that  an  excess  of  adrenine  may 
be  secreted  into  the  blood  as  the  result  of  excitation  of  the  suprarenal 
medulla  by  extracts  of  the  posterior  lobe  of  the  pituitary. 


72  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

Relation  of  pituitary  to  the  sexual  glands. — The  relationship  of  the 
pituitary  to  the  sexual  glands  and  secondary  sexual  characters  has  been 
dealt  with  in  considering  the  symptoms  associated  with  hypo-  and  hyper- 
pituitarism,  and  besides  the  effect  of  these  conditions  on  the  state  of  devel- 
opment of  the  sexual  organs,  the  latter  appear  to  have  some  reciprocal 
effect  on  the  pituitary.  Thus  several  observers  have  found  enlargement 
of  the  gland  and  increase  in  the  number  of  oxyphil  cells  of  the  pars 
ariterior  to  occur  as  the  result  of  castration ;  although  Biedl  and  Fichera 
and  Zacher  describe  the  enlargement  in  the  rat  as  being  produced  by  the 
appearance  of  large  bladder-like  cells,  which  have  not  oxyphil  granules. 
Livingston,  who  has  recently  made  experiments  on  this  subject  in  rab- 
bits, finds  that  the  effect  which  is  produced  is  greater  in  females  than  in 
males,  being  practically  negligible  in  the  latter.  Steinach  and  Scheidt 
state  that  the  changes  in  the  pituitary  which  would  result  from  castra- 
tion are  prevented  by  implantation  of  either  ovary  or  testis  in  the  cas- 
trated animal  and  since  the  generative  cells  of  the  implanted  organs  un- 
dergo atrophy  they  ascribe  the  result  to  the  interstitial  cells.  Moreover, 
it  is  found  that  the  conditions  of  menstruation  and  pregnancy  are  asso- 
ciated with  hypertrophy  of  the  gland.  Indeed,  as  the  result  of  pregnancy 
it  may  attain  to  twice  or  three  times  its  normal  weight. 

CHANGES  IN  THE  PITUITARY  AS  THE  RESULT  OF  THYROIDECTOMY. 

Relation  to  the  thyroid. — That  after  the  removal  of  the  thyroid  th,e 
pituitary  body  becomes  markedly  altered  and  enlarged  was  first  shown 
by  Rogowitsch  in  1886.  His  statements  have  been  abundantly  confirmed 
by  other  observers.*  The  hypertrophy  affects  all  parts,  but  most  the 
pars  anterior,  in  which  it  is  not  uncommon  to  observe  a  development  of 
colloid-containing  vesicles  not  unlike  those  of  the  thyroid:  the  same 
appearance  is  seen  in  cases  of  myxoedema  and  others  involving  patho- 
logical changes  in  the  thyroid  in  the  human  subject  (Boyce  and  Beadles 
and  others).  But  the  pituitary  colloid  is  not  identical  with  that  of  the 
thyroid.  It  is  noteworthy  that  it  does  not  contain  iodine,  which  is  a 
characteristic  component  of  the  thyroidal  colloid  in  all  animals.  Even 
many  months  after  thyroid  removal  Sutherland  Simpson  and  Andrew 
Hunter  were  unable  to  detect  the  least  trace  of  iodine  in  the  sheep 's  pitui- 
tary. Nor  can  the  pituitary  take  the  place  of  the  thyroid  in  animals 
affected  with  cachexia  thyreopriva.  There  is,  therefore,  no  clear  evidence 


*A.  E.  Livdngston  has  found  that  thyroid  feeding  prevents  the  increase  in 
size  of  the  pituitary  which  would  be  caused  by  thyroidectomy.  Halpenny  and 
Thompson  obtained  enlargement  and  other  changes  of  the  pituitary  as  the  re- 
sult of  parathyroidectomy  alone. 


THE   PITUITARY    BODY  73 

that  these  two  organs  act  vicariously:  the  effect  of  the  injection  of  their 
extracts  is,  moreover,  entirely  different.  But  that  they  have  a  certain 
similarity  of  function  in  relation  to  growth  and  development  is  shown 
by  the  results  of  their  removal  in  young  animals.  In  both  cases  growth 
is  slowed  or  arrested,  the  development  of  the  body  generally  and  of  the 
sexual  organs  in  particular  is  checked  and  that  of  the  higher  functions  of 
the  nervous  system  is  interfered  with.  There  is  also  a  tendency  to  adi- 
posity, which  is  particularly  marked  in  cases  of  hypophysial  deprivation, 
but  is  also  seen  after  thyroidectomy  and  in  myxoedema. 

Another  striking  effect  of  thyroidectomy  upon  the  pituitary  is  in- 
crease of  hyaline  and  granular  masses  in  the  pars  intermedia  and  their 
passage  in  large  numbers  through  the  pars  nervosa  into  the  infundibular 
extension  of  the  third  ventricle  (Herring).  This  denotes  an  increased 
activity  of  the  pars  intermedia.  Whether  the  phenomenon  also  occurs  in 
cases  of  myxoedema  has  not  been  noted,  but  it  will  probably  be  found  to 
be  the  case. 

Relation  of  the  pituitary  to  organs  concerned  with  carbohydrate 
metabolism. — Hypopituitarism,  whether  the  result  of  disease  or  of  sur- 
gical interference,  is  associated  with  an  increased  tolerance  for  sugar. 
This  function  is,  as  we  have  seen,  connected  with  the  posterior  lobe.  Ac- 
cording to  Gushing,  animals  which  have  suffered  deprivation  of  this  lobe 
will  even  bear  removal  of  the  pancreas  without  exhibiting  glycosuria. 
But  the  result  of  removing  the  pancreas  in  causing  glycosuria  is  pro- 
duced through  the  liver,  the  glycogen  of  which  becomes  converted  into 
sugar.  And  an  effect  similar  to  removal  of  the  pancreas  is  produced  by 
excess  of  adrenine  in  the  blood  or  by  swabbing  the  exposed  pancreas 
with  adrenine  solution. 

Gushing  states  that  after  removal  of  the  pancreas  the  amount  of 
hyaline  substance  of  the  pars  intermedia  and  pars  nervosa  is  increased. 
All  this  seems  to  show  that  there  exists  a  close  functional  correlation  be- 
tween these  four  organs — pituitary,  suprarenal,  pancreas,  and  liver,  and 
that  disturbance  of  the  function  of  one  of  them  may  affect  the  metab- 
olism of  carbohydrates  through  its  influence  upon  others.  And  to  these 
we  may  add  the  thyroid,  since,  as  has  already  been  noticed,  the  mechan- 
ism of  carbohydrate  metabolism  is  also  affected,  in  some  manner  as  yet 
imperfectly  understood,  by  a  condition  of  hypothyroidism,  which,  like 
hypopituitarism,  raises  the  assimilation  limit  for  sugar  in  the  body ;  and 
on  the  other  hand,  as  the  experiments  of  Asher  and  Flack  have  shown, 
the  presence  of  an  unusual  amount  of  thyroid  secretion  in  the  blood  acts 
as  an  excitant  to  the  suprarenals  so  that  an  increased  outpouring  of 
adrenine  is  caused,  and  this  produces  a  lowering  of  the  sugar  assimila- 
tion limit. 


74  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

It  is,  however,  upon  two  of  the  externally  secreting  glands  that  the 
most  obvious  effect  of  the  autacoid  or  autacoids  derived  from  the  posterior 
lobe  of  the  pituitary  is  exhibited.  These  are  the  kidney  and  the  mam- 
mary gland.  The  effect  on  the  kidney  is  a  specific  one  and  may  be  here 
more  fully  alluded  to. 

Effect  of  pituitary  autacoid  upon  the  kidney. — If  the  blood-pressure 
of  an  animal  is  measured  in  the  usual  way  by  a  manometer  and  at  the 
same  time  the  volume  of  the  kidney  and  the  rate  of  urine  flow  are  re- 
corded, it  is  found  that  on  injecting  extract  of  the  posterior  lobe  or  an 
aqueous  solution  of  its  autacoids  into  a  vein,  whilst  the  normal  rise  of 
blood-pressure  is  obtained  owing  to  a  general  constriction  of  the  arterioles 
of  the  body,  this  constriction  is  not  shared — or  only  for  a  very  brief 
interval* — by  the  kidney,  but  is  here  replaced  by  a  dilatation  which  shows 
itself  by  expansion  of  the  organ  enclosed  in  an  oncometer.  Accompany- 
ing this  expansion,  a  remarkable  increase  in  the  amount  of  urine  is 
observed;  or  if,  as  often  happens  after  such  operation  in  an  anaesthized 
animal,  there  is  no  urine  being  secreted  before  the  administration  of  the 
autacoid,  the  flow  speedily  begins,  and  continues  at  a  rapid  although  a 
slowly  diminished  rate,  for  a  prolonged  period  of  time.  It  might  at  first 
be  supposed  that  the  increase  of  urine  is  simply  determined  by  the  great 
increase  of  blood-flow  through  the  organ  consequent  upon  the  general 
vaso-constriction  and  the  local  vaso-dilatation  which  pituitary  extract 
produces.  But  it  may  be  seen  that  increased  rate  of  flow  is  still  main- 
tained after  the  blood-pressure  has  come  back  to  the  level  at  which  it 
stood  before  the  injection.  Moreover,  the  effect  of  a  second  and  sube- 
quent  doses  of  the  autacoid  administered  soon  after  the  main  result  of  the 
first  dose  has  passed  off  again  produce  an  increase  in  the  urine  flow, 
although  the  blood-pressure  as  the  result  of  these  after-doses  does  not 
rise,  or  even  falls  instead  of  rising,  and  although  the  kidney  volume  may 
now  be  unaffected.  This  experiment  clearly  demonstrates  that  the  auta- 
coid may  affect  not  only  the  bloodvessels  of  the  organ,  but  also  its  secret- 
ing cells,  which  it  renders  more  active  (or  more  permeable).  The  secre- 
tion must  therefore  in  these  circumstances  be  induced  by  a  direct  chemi- 
cal excitation  of  the  renal  cells  by  the  autacoid,  which  thus  bears  the 
same  relation  to  the  kidneys  as  is  borne  by  the  secretine  of  the  duodenum 
to  the  pancreas.  In  this  respect  also  the  action  of  the  autacoid  of  the 
pituitary  is  comparable  to  that  of  those  drugs  which  act  as  specific  diuret- 
ics upon  the  secreting  cells  of  the  kidney,  as  distinguished  from  those 


*During  this  preliminary  period  the  flow  of  urine  may  be  temporarily  di- 
minished or  arrested. 


THE  PITUITARY   BODY  75 

which  produce  diuresis  by  increasing  the  water  content  of  the  blood  or 
by  merely  increasing  the  general  blood-pressure.  The  question  arises 
whether  we  have  to  do  here  with  the  action  of  a  single  autacoid  which 
acts  on  the  one  hand  as  a  chalone  upon  the  bloodvessels  of  the  organ  pro- 
ducing their  dilatation,  and  on  the  other  as  a  hormone  upon  the  secret- 
ing cells  stimulating  them  to  increased  activity,  or  whether  two  separate 
autacoids  are  concerned,  one  of  which  affects  the  bloodvessels  and  the 
other  the  cells  of  the  organ.  The  latter  view  was  taken  by  Herring  and 
myself,  but  has  been  combated  by  Dale,  who  adduces  other  examples  of 
the  action  of  drugs  and  extracts  in  which  the  same  active  substance  may 
produce  a  double  result,  one  part  of  which  may  fail  to  show  itself.  If 
Dale's  contention  is  correct  we  are,  so  far  as  the  action  upon  the  kidney 
and  its  vessels  is  concerned,  dealing  with  a  single  autacoid  capable  of  act- 
ing either  upon  both  tissues,  viz.,  bloodvessels  and  secreting  cells,  or  upon 
one  only.  When  its  action  is  produced  upon  one  only  this  may  then  be 
interpreted  to  mean  that  the  other  is  temporarily  insensitive  to  its  action : 
for  example,  in  the  case  of  the  action  of  pituitary  autacoid  upon  the 
kidney  one  may  sometimes  observe  that  the  diuretic  action  (upon  the 
cells)  fails  to  be  produced  whilst  the  vascular  effects  are  pronounced. 
But  even  if  this  were  correct  for  the  kidney,  it  need  not  commit  us  to 
the  conclusion  that  pituitary  extract  contains  only  one  autacoid.  For 
there  is  reason  to  think  that  a  distinct  autacoid  affects  the  secretion  of 
milk;  and  the  fall  of  blood-pressure  produced  by  a  second  dose  of  pitui- 
tary extract  (see  p.  58)  is  probably  due  to  another;  and  quite  possibly 
the  effects  upon  the  uterus  to  a  third.  Baya  and  Peter  have  also  given 
evidence  for  the  belief  that  there  are  two  autacoids  which  act  upon  the 
intestinal  muscle,  one  producing  inhibition  and  the  other  contraction: 
they  state  that  they  are  separable  by  alcohol. 

The  diuretic  action  of  the  pituitary  autacoid  is  not  antagonized  by 
atropine.  This  may  be  taken  to  be  a  sign  that  it  does  not  act  through 
nerves  or  nerve-endings,  but  directly  upon  the  kidney  cells;*  in  this 
respect  it  resembles  the  action  of  secretine  upon  the  pancreas. 

Effect  of  extract  of  posterior  lobe  of  pituitary  upon  the  mammary 
gland. — It  was  shown  by  Ott  and  Scott  that  in  the  goat  an  injection  of 
this  extract  into  a  vein  greatly  increases  the  quantity  of  milk  which  can 
be  drawn  from  the  udder  in  a  given  time  after  the  injection,  as  compared 


*It  is  usually  held  that  the  renal  secretion  is  independent  of  a  direct  influ- 
ence of  nerves  upon  the  secreting  cells — thus  differing  from  ordinary  secreting 
glands,  such  as  the  salivary  glands.  But  Asher  has  recently  adduced  evidence 
which  appears  to  indicate  that  influences  passing  down  the  vagus  nerve  may 
affect  the  quantity  of  urine  secreted  by  the  homolateral  kidney. 


76  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

with  that  which  could  be  obtained  in  a  similar  period  immediately  before. 
This  galactagogue  action  of  pituitary  extract  was  confirmed  by  experi- 
ments upon  lactating  cats  by  Mackenzie  and  myself.  The  method  we 
employed  consisted  in  canalizing  or  incising  the  nipple  of  one  or  two  of 
the  mammae  so  as  to  allow  any  milk  which  was  secreted  to  run  out.  This 
was  conducted  to  the  side  and  registered  by  allowing  it  to  fall  upon  an 
electrical  drop  recorder.  This  modus  operandi  permits  the  conditions  of 
the  experiment  to  be  readily  controlled  and  the  results  to  be  accurately 
registered.  It  can  thus  be  shown  that  even  a  very  minute  dose  of  a  pitui- 
tary autacoid — whether  the  same  as  that  which  affects  the  bloodvessels 
and  produces  increased  secretion  of  urine  cannot  certainly  be  said — will 
cause  milk  which  has  accumulated  in  the  gland  to  be  immediately  poured 
out,  whilst  a  somewhat  larger  dose  will  produce  complete  emptying  of  the 
alveoli.  If  the  nipple  be  not  canalized  or  incised,  the  resistance  which  is 
afforded  in  the  passage  through  its  ducts,  controlled  as  they  are  by  the 
plain  muscle  tissue  which  abounds  in  the  nipple,  does  not  permit  of  this 
emptying  and  no  actual  outpouring  of  the  secretion  takes  place.  If  an 
intramuscular  injection  of  pituitary  extract  is  made  in  the  arm  of  a 
nursing  woman,  a  feeling  of  tingling  is  felt  in  the  mamma  and  a  sensa- 
tion of  milk  flowing  towards  the  nipple  is  experienced  like  that  which 
occurs  when  the  child  is  put  to  the  breast,  but  there  is  no  actual  outpour- 
ing of  the  secretion. 

If  in  the  experiment  upon  the  cat  the  animal  be  killed  immediately 
after  one  of  its  glands  (with  nipple  incised)  has  been  emptied  by  an 
intravenous  injection  of  extract  of  posterior  lobe  in  the  manner  above  de- 
scribed, and  if  a  portion  of  tissue  comprising  parts  of  two  adjacent 
mammae — one  emptied  of  its  secretion  as  the  result  of  the  injection,  the 
other  with  its  alveoli  still  full  of  milk — be  fixed  and  sections  made  passing 
through  both  full  and  empty  mammae,  the  contrast  in  appearance  is  re- 
markable. In  the  one,  where  the  alveoli  are  distended  with  secretion,  they 
are  large  and  rounded  and  the  lining  cells  are  flattened  against  the  limit- 
ing membrane,  whilst  in  the  other  from  which  the  secretion  has  been  dis- 
charged the  alveoli  are  irregular,  shrunk  and  empty  and  their  cells  are 
folded,  and  the  lining  cells  stand  prominently  out  from  the  limiting 
membrane. 

If  after  a  first  full  dose  of  pituitary  extract  has  been  given  a  second 
dose  succeed  it  at  a  short  interval,  no  further  flow  of  secretion  from  the 
exhausted  mamma  can  be  produced.  The  effect  of  the  autacoid,  there- 
fore, is  not — at  any  rate  immediately — to  cause  the  cells  to  form  and 
secrete  milk,  but  only  to  cause  the  alveoli  to  empty  themselves  of  the  milk 
which  has  been  previously  formed  and  secreted  within  them.  The  sim- 


THE   PITUITARY    BODY  77 

plest  manner  in  which  one  can  conceive  this  to  occur  is  by  contraction  of 
(plain)  muscular  tissue  around  the  alevoli.  In  support  of  this  opinion  I 
have  lately  succeeded  in  observing  in  the  well  of  the  mammary  alveolus  in 
the  cat  long  rod  shaped  nuclei  immediately  external  to  the  epithelium. 
These  nuclei  exactly  resemble  those  of  involuntary  muscle-cells  and  I  have 
no  doubt  that  they  belong  to  a  thin  muscular  layer  which,  like  the  muscu- 
lar tissue  of  the  sweat-glands,  is  probably  situated  between  the  basement 
membrane  and  the  epithelium  of  the  alveoli. 

The  action  of  pituitary  extract  upon  milk  secretion  differs  from  its 
effect  upon  the  secretion  of  urine  in  the  fact  that  in  the  last  named  case 
there  is  an  actual  stimulation  of  the  renal  cells  to  abstract  fluid  from  the 
blood,  and  not  a  mere  contraction  of  alveoli  and  outpouring  of  previously 
secreted  fluid. 

Apart  from  the  pouring  out  of  the  contents  of  the  alveoli — or  rather 
the  tendency  of  the  alveoli  to  empty  themselves  towards  the  nipple — 
which  is  excited  by  the  pituitary  galactagogue,  there  is  but  little  tendency 
to  cause  an  increased  production  of  milk.  This  at  least  is  the  result  which 
was  obtained  in  cows  by  Gavin.  Later  observers  (Hammond  and  Suther- 
land Simpson)  have  obtained  a  slight  increase  in  the  diurnal  yield  of  both 
goats  and  cows  and  also  a  slightly  increased  amount  of  fat  in  the  milk 
produced  under  the  influence  of  the  autacoid. 

Mackenzie  found  that  in  the  cat  atropine  does  not  arrest  the  flow  of 
milk  obtained  as  the  result  of  pituitary  injection  (an  observation  which 
has  been  confirmed  for  the  cow  by  Houssay).  He  obtained,  however,  an 
inhibitory  action  from  extracts  of  placenta,  which,  when  injected  into  a 
vein  just  previously  to  the  injection  of  pituitary  extract,  prevented  the 
effect  of  the  latter  from  influencing  the  mammary  gland.  It  is  reason- 
able to  conclude  from  this  that  placenta  extract  must  contain  a  chalonic 
autacoid  which  restrains  the  outpouring  of  the  secretion  of  the  mamma 
and  antagonizes  the  harmonic  action  of  the  pituitary  autacoid. 

The  mamma  is  much  more  sensitive  to  the  action  of  pituitary  extract 
than  are  other  organs  (except  perhaps  the  uterus)  and  an  outflow  of 
milk  can  be  obtained  with  a  dose  which  produces  no  appreciable  effect  on 
the  blood-pressure  or  kidney.  This  is  well  illustrated  by  an  experiment 
by  Herring  with  the  skate's  pituitary.  In  this  no  effect  was  shown  on 
the  blood-pressure  or  kidney,  but  there  was  abundant  outflow  of  milk. 
Or  it  may  be  that  the  effect  is  due  to  a  special  hormone  and  that  the 
one  which  influences  blood-pressure  and  kidney  secretion  is  absent  in  the 
skate's  pituitary.  The  blood  of  non-lactating  animals  sometimes  con- 
tains enough  of  the  galactagogue  autacoid  to  provoke  the  mammary  secre- 
tion of  a  lactating  animal,  although  the  other  effects  of  pituitary  autacoid 


78  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

are  unseen.  Thus  in  one  experiment  5  c.  c.  of  the  blood-serum  of  a 
guineapig  was  injected  into  a  lactating  cat  and  provoked  a  marked  secre- 
tion from  a  mamma  the  nipple  of  which  had  been  incised,  although  no 
effect  on  the  blood-pressure  was  obtained. 

Galactagogue  autacoids  are  also  contained  in  extracts  of  other  organs  than 
the  pituitary,  viz:  the  corpus  luteum  of  the  ovary,  the  involuting  mucous 
membrane  of  the  uterus  after  parturition,  the  lactating  mammary  gland  itself, 
and  to  a  slight  extent  from  the  pineal  gland.  Their  effect  on  the  mamma  is 
exactly  like  that  of  the  pituitary  galactagogue,  but  the  effects  on  blood-pressure 
are  either  nil  or  are  different  from  that  of  pituitary  extract.  It  is  possible  that 
in  all  these  cases  the  galactagogue  autacoid  is  the  same  as  that  obtainable 
from  the  pituitary. 

The  effect  of  galactagogue  extracts  in  causing  secretion  from  the  gland  is 
accompanied  by  a  change  in  the  electric  potential  of  the  organ  so  that  the 
alveoli  tend  to  become  negative  to  the  duct.  This  change  is  somewhat  similar 
to  that  which  is  produced  in  the  submaxillary  gland  as  the  result  of  exciting 
the  chorda  tympani. 

From  what  has  been  stated  regarding  the  mammary  gland,  it  is  obvious 
that  this  is  an  organ  which  is  singularly  under  the  influence  of  autacoids  circu- 
lating in  the  blood.  It  is,  moreover,  well  known  that  its  secretion  is  not  directly 
under  the  influence  of  nerves.  Excitation  of  its  nerves  is  not  found  to  produce 
any  effect  on  the  secretion — which,  moreover,  continues  normal  after  all  nerves 
are  cut  ^Eckard)  and  even  from  a  gland  which  has  teen  transplanted  to  a  totally 
different  situation  (Ribbert).  Moreover,  the  case  of  the  pyophagus  twins,  Rosa- 
Josepha  Blazek,  who  are  united  by  a  common  sacrum,  with  anus  and  vulva  in 
common  but  with  two  uteri  and  vaginae,  is  particularly  interesting  in  connec- 
tion with  this  question.  For  when  one  of  the  twins  became  pregnant  the  mam- 
mary gland  in  both  underwent  hypertrophy  and  eventually  secreted  milk.  The 
well-known  effects  of  nervous  conditions  (emotions  and  the  like)  upon  milk 
secretion  must  therefore  be  produced  through  the  internal  secretions  of  organs 
such  as  the  pituitary.  That  emotions  may  act  in  this  way  is  shown  by  the 
experiments  of  Cannon  (already  referred  to),  who  determined  an  increase  of 
adrenine  in  the  blood  of  a  cat  which  had  been  excited  by  the  presence  of  a 
strange  dog. 


THE   PINEAL   GLAND,   THE  PANCREAS,  ETC.  79 

LECTURE  V. 

THE  INTERNAL  SECRETIONS  OF  THE  PINEAL  GLAND,  OP  THE  ALIMENTARY 
Mucous  MEMBRANE,  OF  THE  PANCREAS,  AND  OF  THE  SEXUAL  ORGANS. 

The  internal  secretion  of  the  pineal  gland. — The  pineal  gland  or 
epiphysis  cerebri  (conarium),  which  is  present  in  nearly  all  vertebrates, 
is  in  man  a  small  solid  organ  less  than  half  the  size  of  the  pituitary  body. 
It  projects  from  the  roof  or  dorsal  wall  of  the  third  ventricle  and  is  con- 
nected on  either  side  by  a  short  stalk  or  peduncle  to  the  habenular  com- 
missure. The  base  of  the  gland  has  a  small  infundibular  depression 
(pineal  recess)  leading  from  the  ventricle  just  above  the  entrance  of  the 
aqueduct.  This  recess  is  the  remains  of  the  evagination  from  the  third 
ventricle,  from  which  the  pineal  was  originally  developed.  The  gland  is 
somewhat  larger  in  the  child  than  in  the  adult,  and  in  the  female  than  in 
the  male.  Its  average  weight  is  given  as  0.22  grm.  in  man.  It  lies  back 
between  the  anterior  pair  of  corpora  quadrigemina,  and  is  closely  in- 
vested by  pia  mater,  usually  becoming  detached  from  the  brain  when  the 
pia  mater  is  torn  away. 

Structure. — Sections  of  the  pineal  show  it  to  be  composed  of  epithe- 
lium-like cells  arranged  in  irregularly  disposed  trabeculse  with  connective 
tissue  between.  In  some  animals  plain  muscular  tissue  has  been  de- 
scribed in  the  intertrabecular  tissue.  The  bloodvessels  are  very  numer- 
ous. There  are  no  true  nervous  elements,  with  the  exception  of  a  few 
fibres  apparently  destined  for  the  bloodvessels,  but  neuroglia  cells  are 
present  in  the  septa  and  are  said  to  increase  in  number  with  age.  Em- 
bedded in  the  interstitial  tissue  and  in  the  covering  of  the  pia  mater  are 
small  round  globules  of  calcareous  matter — corpora  amylacea,  brain  sand 
— which  are  much  more  common  in  man  than  in  other  animals  and  more 
numerous  in  the  adult  than  in  the  child.  The  cells  of  the  organ  are  not 
everywhere  uniform  in  character.  Most  of  them  have  a  large  oval  nucleus 
and  a  variable  number  of  fine  oxyphil  granules  in  their  protoplasm,  but 
some  possess  basophil  granules.  Comparatively  large  oxyphil  granules 
such  as  are  seen  in  the  anterior  part  of  the  pituitary  are  not  found  in  the 
pineal,  which  otherwise  is  not  very  dissimilar  in  general  appearance  to 
that  portion  of  the  pituitary  in  structure,  although  less  vascular.  Ves- 
icles containing  "colloid"  are  not  present,  but  cysts  are  not  infrequent: 
these  may  be  due  to  pathological  changes.  The  gland  undergoes  retro- 
gressive changes  after  puberty:  these  take  the  form  of  hypertrophy  of 
the  intertrabecular  tissue  with  diminution  in  the  amount  of  epithelial 
tissue:  nevertheless  this  last  remains  present  to  some  extent  through- 
out life. 


80  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

Ott  and  Scott  found  that  the  result  of  intravenous  injection  of 
extract  of  pineal  is  to  produce  a  fall  of  blood-pressure  followed  by  a  pro- 
longed rise  with  dilatation  of  kidney  volume  and  diuresis.  They 
obtained  some  increase  of  contraction  of  the  uterus.  They  state  that 
dilatation  of  the  pupil  is  produced  on  dropping  the  extract  into  the  eye 
of  an  animal  in  which  the  superior  arterial  ganglion  had  been  extirpated. 
They  further  noticed  that  the  extract  has  a  slight  galactagogue  action. 
All  these  effects  are  similar  to  those  produced  by  pituitary  extract.  The 
galactagogue  action  described  has  been  since  confirmed  by  Mackenzie,  but 
Dixon  and  Halliburton  obtained  no  result  so  far  as  arterial  pressure  and 
kidney  secretion  is  concerned,  apart  from  a  slight  fall  of  blood-pressure, 
which  was  almost  entirely  non-specific.  My  own  experiments  have  yielded 
negative  results  in  these  particulars  and  those  of  Jordan  and  Eyster  were 
also  negative. 

Extirpation  of  the  pineal  is  a  difficult  operation  to  carry  through 
without  provoking  severe  haemorrhage,  to  which  the  animals  operated  on 
have  generally  succumbed.  The  most  complete  series  of  experiments  as 
yet  made  are  those  of  Foa  on  the  domestic  fowl.  In  pullets  in  which  the 
pineal  gland  was  destroyed  no  difference  could  be  noted  on  comparison 
with  controls,  but  in  cockerels  Foa  describes  not  only  a  more  rapid  growth 
of  body  but  an  earlier  development  of  the  testicles  and  of  the  secondary 
sexual  characters. 

The  accounts  of  the  results  of  castration  on  the  pineal  have  been 
conflicting.  Those  of  Sarteschi  on  male  animals  of  several  different 
species  proved  negative :  whereas  Biach  and  Huller  describe  in  cats,  both 
male  and  female,  the  production  of  an  atrophied  condition  of  the  pineal 
as  the  result  of  the  removal  of  the  generative  glands.  In  connexion  with 
this  it  is  interesting  to  notice  that  Schiiller  and  other  clinical  observers 
have  described  abnormal  growth  of  the  skeleton  and  sexual  precocity, 
with  early  development  of  secondary  sexual  characters,  in  young  boys, 
before  the  seventh  year,  in  whom  tumour  of  the  pineal — generally  of  the 
nature  of  a  teratoma — has  been  discovered  post  mortem.  In  some  of  the 
cases  in  which  secondary  sexual  characters  were  present  the  testicles  had 
remained  small,  but  there  was  an  unusually  large  amount  of  the  inter- 
stitial tissue.  The  symptoms  have  been  ascribed  to  a  diminution  of  func- 
tion of  the  pineal.  Another  condition  which  has  been  frequently  noted 
as  accompanying  pineal  tumours  is  unusual  adiposity,  of  a  somewhat 
similar  nature  to  that  accompanying  hypopituitarism,  but  not  as  a  rule 
associated  with  deficient  development  of  the  generative  organs.  It  has 
been  suggested  that  this  may  be  caused  by  a  condition  of  hyperpinealism. 
But  it  must  be  admitted  that  both  clinical  observations  on  the  subject  and 
experimental  observations  in  animals  are  at  present  too  fragmentary  to 


THE   PINEAL   GLAND,   THE  PANCREAS,   ETC.  81 

enable  us  to  decide  with  any  precision  regarding  the  functions  of  this 
organ  or  the  nature  and  action  of  its  autacoids. 

Internal  secretions  of  the  mucous  membrane  of  the  alimentary  canal. 
— Bayliss  and  Starling  discovered  in  1902  that  an  extract  of  the  duodenal 
mucous  membrane  or  even  of  its  epithelium  alone,  if  injected  into  the 
circulating  blood,  produces  a  secretion  of  pancreatic  juice  and,  to  a 
less  marked  degree,  of  bile.  In  Bayliss  and  Starling's  experiments  the 
active  substance  or  autacoid  was  obtained  by  boiling  the  mucous  mem- 
brane with  dilute  hydrochloric  acid  and  afterwards  neutralizing  and 
filtering:  the  autacoid  is  contained  in  the  filtrate.  They  observed  little 
or  no  activity  from  extracts  of  membrane  which  had  not  been  treated 
with  acid,  and  concluded  that  the  hormone  (secretine)  is  present  in  the 
cells  in  an  inactive  form  (pro-secretine)  and  becomes  activated  (converted 
into  secretine)  by  the  action  of  the  acid.  It  had  been  previously  found 
that  rinsing  the  duodenum  with  dilute  mineral  acid*  would  provoke  secre- 
tion of  pancreatic  juice.  This  had  been  put  down  to  a  reflex  effect 
through  nerves  and  nerve-centers,  but  the  experiments  of  Bayliss  and 
Starling  make  it  clear  that  the  effect  is  due  to  the  formation  arid  absorp- 
tion into  the  blood  of  an  organic  chemical  agent  of  a  fairly  simple  con- 
stitution— being  dialyzable  and  not  destroyed  by  boiling. 

That  there  is  mutual  interaction  between  pancreas  and  duodenum 
would  appear  from  the  observations  of  Evans,  who  found  that  pro- 
secretine  disappears  from  the  duodenum  after  complete  extirpation  of 
pancreas,  but  not  if  enough  pancreas  be  left  to  prevent  the  occurrence  of 
glycosuria. 

In  1906  Edkins  announced  that  a  substance  of  similar  nature  to 
secretine  but  acting  upon  the  glands  of  the  stomach  can  be  extracted 
from  the  pyloric  mucous  membrane  by  boiling  water  or  dilute  hydro- 
chloris  acid,  or  with  dextrose,  maltose  or  albumose.**  Extracts  of  the 
mucous  membrane  of  the  fundus  do  not  yield  a  similar  hormone. 

Atropine,  which  in  small  doses  acts  through  the  nerve-endings  of  secreting 
organs,  does  not  inhibit  the  action  of  these  secretines  and,  as  we  have  seen, 
neither  does  it  inhibit  the  action  of  the  galactagogue  autacoids.  Their  activity 
is,  therefore,  probably  manifested  directly  upon  the  cells  of  the  organ  they 
stimulate  and  not  through  the  nerve  terminations. 

The  internal  secretion  of  the  pancreas. — The  pancreas  contains,  be- 
sides its  alveoli  and  the  ducts  which  conduct  their  secretion  into  the  duo- 


*According  to  Babkin  and  Ishikawa,  fatty  acids  introduced  into  the  duo- 
denum have  a  similar  effect. 

**Albumose  has  been  found  by  Gley  also  to  activate  the  pro-secretine  of  the 
duodenum. 


82  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

denum,  a  peculiar  epithelial  tissue  occurring  in  most  animals  in  the  form 
of  small  isolated  masses  interspersed  throughout  the  gland,  and  known 
from  their  discoverer  (1869)  as  the  islefts  of  Langerhans.  Although  quite 
distinct  in  appearance  and  in  the  characters  of  their  cells  from  the  epithe- 
lium of  the  alveoli,  the  study  of  their  development  shows  that  they 
originally  grew  out  from  the  budding  ducts  and  that  their  cells  have 
therefore  an  origin  in  common  with  those  of  the  alveoli.  But  they  have 
no  open  communication  with  the  ducts  or  alveoli.  The  number  of  islets 
in  the  pancreas  is  very  variable,  and  this  variability  has  led  to  inferences 
being  drawn  regarding  their  appearance  and  disappearance,  which  in 
many  cases  are  probably  not  justifiable.  Thus  Bensley  found  a  variation 
in  the  guineapig  in  animals  of  different  ages  of  from  10  to  189  islets  per 
milligramme  of  pancreas:  in  the  mature  animal  the  variation  was  from 
10  to  25.  The  enumerations  of  Clerk  led  him  to  the  conclusion  that  in 
the  normal  human  pancreas  there  may  be  as  many  as  10  to  20  islets  in 
each  milligramme  of  the  gland,  which  roughly  would  give  about  three- 
quarters  of  a  million  to  a  million  and  a  half  for  the  whole  pancreas. 

In  Teleostean  fishes  Rennie  has  shown  that  there  is  one  very  large 
mass  of  islet  tissue  which  is  encapsuled  by  connective  tissue  and  prac- 
tically forms  a  separate  organ.  But  in  other  animals  the  islets  are  closely 
encircled  by  and  in  contact  with  the  alveolar  tissue  and  sometimes  appear 
to  be  contined  into  it.  According  to  Pensa,  they  have  an  especially 
abundant  nerve  supply.  Each  islet  has  a  specialized  blood-supply  in  the 
form  of  a  network  of  irregular  shaped  ' '  sinusoidal ' '  capillaries  which  are 
both  larger  and  relatively  more  numerous  than  the  capillaries  of  the 
alveoli  (Kuhne  and  Lea). 

The  cells  of  the  islets  are  generally  much  less  stained  by  the  ordinary 
dyes  used  in  histology  than  are  those  of  the  alveoli.  They  are  therefore 
usually  described  as  chromophobe.  But  they  have  an  especial  affinity,  as 
Bensley  has  shown,  for  neutral  red  and  janus  green,  employed  as  intra- 
vital  stains.  Although  they  contain  granules,  these  are  much  finer  than 
the  zymogen  granules  of  the  alveolar  cells.  According  to  Lane,  there 
are  two  kinds  of  cells  in  the  islets,  distinguishable  from  one  another  by 
the  nature  of  their  granules.  The  cells  come  into  very  close  relation — 
indeed,  in  actual  contact — with  the  walls  of  the  blood  capillaries.  If  the 
duct  of  the  pancreas  be  tied,  the  ordinary  alveolar  tissue,  after  a  time, 
disappears,  although  for  a  long  while  after  there  are  the  remains  of  the 
chief  ducts  passing  through  the  organ,  but  most  observers  are  agreed  that 
the  islet  tissue  does  not — at  least  to  any  great  degree — participate  in  the 
atrophy  of  the  alveoli,  and  the  statement  that  its  persistence  under  these 
circumstances — although  denied  by  some — is  generally  accepted, 


THE   PINEAL   GLAND,   THE  PANCREAS,  ETC.  83 

although  it  must  be  admitted  that  in  the  altered  and  cirrhosed  tissue  of 
the  gland  it  is  not  easy  to  recognize  the  distinctive  features  of  the 
islet-cells. 

Since  the  discovery  in  1889  by  v.  Mering  and  Minkowski,  that  the 
removal  of  the  pancreas,  or  even  of  the  greater  part  of  the  organ,  is 
immediately  followed  by  hyperglycaemia  leading  to  severe  and  fatal 
diabetes,  whereas  this  effect  is  not  obtained  from  mere  ligature  of  the 
duct  (in  spite  of  the  disappearance  of  all  the  alveolar  tissue  and  the 
complete  cessation  of  formation  of  pancreatic  juice),  attention  has  been 
especially  directed  to  the  islet-tissue  as  the  probable  source  of  an  internal 
secretion  which  serves  to  regulate  carbohydrate  metabolism.  For,  as  has 
just  been  stated,  the  cirrhosed  and  atrophied  gland  which  remains  after 
ligature  of  the  duct  contains  none  of  the  ordinary  secreting  epithelium, 
except  perhaps  that  of  a  few  remaining  ducts,  but  does,  in  all  prob- 
ability, still  contain  the  islets  of  Langerhans.  Nevertheless  this  atrophied 
gland  is  sufficient  to  furnish  the  autacoid  which  regulates  carbohydrate 
metabolism,  which  is  by  it  maintained  normal  for  an  indefinite  time.  But 
if  now  the  atrophied  gland  is  removed,  diabetes  at  once  shows  itself.  Fur- 
ther, if  a  portion  of  pancreas — whether  thus  atrophied  or  not' — be  suc- 
cessfully transplanted  to  another  site  and  the  rest  of  the  gland  be  then 
removed,  diabetes  does  not  occur — although,  on  removal  of  the  graft,  it 
immediately  makes  its  appearance.  The  evidence  for  the  action  of  an 
internal  secretion  which  is  yielded  by  the  gland — and  in  all  probability 
by  the  islet- tissue — which  serves  to  maintain  carbohydrate  metabolism  in 
a  normal  condition  is  therefore  very  complete.  In  support  of  this  con- 
clusion it  has  frequently  been  noted  in  cases  of  diabetes  in  man  that  the 
cells  of  the  islets  have  undergone  some  kind  of  degenerative  change. 

Regarding  diabetes  resulting  from  experimental  removal  of  the  pan- 
creas, it  may  be  remarked  in  the  first  place  that  if  the  removal  is  com- 
plete the  percentage  of  sugar  in  the  urine  is  very  large,  even  during  fast- 
ing or  on  carbohydrate  free  diet.  Minkowski  found  the  relation  of  dex- 
trose to  nitrogen  in  the  dog  under  these  circumstances  to  be  2.8 :1.  With 
protein  diet  the  sugar  rises  (and  falls)  with  the  nitrogen:  with  fatty 
foods  there  is  an  increase  in  the  quotient:  carbohydrates  of  the  food 
are  almost  wholly  passed  out  by  the  urine  as  dextrose.  Laevulose  is,  how- 
ever, to  a  great  extent  utilized  in  the  body  and  the  glycogen  which  had 
disappeared  from  the  liver  and  muscles  may  to  some  extent  reappear 
when  this  sugar  is  given  with  the  food. 

The  glycosuria  is  accompanied  by  hyperglycaemia,  which  is  indeed 
the  actual  cause  of  the  glycosuria;  but  according  to  de  Meyer  it  is  aug- 
mented by  the  fact  that  the  permeability  of  the  kidneys  to  blood-sugar 


84  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

seems  also  to  be  somewhat  increased  by  absence  of  the  pancreas.  The-' 
nyperglycaemia  is  produced  in  the  first  instance  by  transformation  of  the 
liver  glycogen  into  sugar,  which  is  passed  into  the  blood ;  while  the  gly- 
cogen  of  the  muscles  is  also  diminished.*  The  sugar  thus  produced  from 
the  liver  glycogen  is  not  utilized  in  the  body,  but  is  for  the  most  part  at 
once  got  rid  of  by  the  kidneys.**  Since,  therefore,  the  carbohydrates  of 
the  food  are  not  used  for  nutrition,  there  is  a  comparatively  greater  call 
upon  the  proteins  and  fats  both  of  the  food  and  of  the  body,  so  that  the 
animal  loses  flesh  rapidly  and  death  may  ultimately  result  from  inanition, 
unless  the  end  has  arrived  sooner  as  the  result  of  the  accumulation  in 
the  body  of  abnormal  byeproducts  of  the  metabolism  of  proteins  and  fats 
(such  as  the  acetone-bodies)  tending  to  acidosis  and  the  production  of 
diabetic  coma. 

The  results  of  pancreas-extirpation  and  pancreas-grafting  can,  as 
we  have  seen,  be  best  explained  by  supposing  that  the  islet-tissue  pro- 
duces an  autacoid  substance  which  passes  into  the  blood  and  affects  carbo- 
hydrate  metabolism  and  carbohydrate  storage  in  such  a  manner  that 
there  is  no  undue  accumulation  of  glucose  in  the  blood.  Provisionally  it 
will  be  convenient  for  descriptive  purposes  to  refer  to  this  hypothetical 
autacoid  as  insuline.  It  must,  however,  be  stated  that  it  has  yet  to  be 
determined  whether  the  active  substance  is  present  as  such  in  the  pan- 
creas or  whether  it  exists  there  as  pro-insuline,  which  becomes  elsewhere 
converted  into  the  active  autacoid.  It  is  not  found  that  pancreas  extracts 
have  the  effect  of  antagonizing  the  results  of  pancreas  extirpation :  in  this 
respect  they  offer  a  parallel  to  the  negative  results  of  suprarenal  extracts 
in  antagonizing  the  effects  of  adrenal  deprivation.  On  the  other  hand,  it 
has  been  shown  by  Hedon  and  by  Forschbach  that  the  blood  of  a  normal 
dog  contains  substances  which  when  allowed  to  circulate  through  the  sys- 
tem of  a  depancreatized  dog  prevent  the  occurrence  of  glycosuria.  It  has 
also  been  shown  by  Carlson  and  Drennan  that  if  a  pregnant  bitch  be 
deprived  of  the  pancreas  she  does  not  suffer  from  glycosuria  as  long  as 
her  foatuses  remain  in  utero.  This  experiment  proves  that  the  autacoids 
produced  by  the  foetal  pancreas  can  pass  to  the  maternal  circulation 
through  the  placenta ;  and  both  experiments  afford  a  clear  indication  that 
the  influence  of  the  pancreas  upon  carbohydrate  metabolism  is  due  to  a 
chemical  agent  circulating  in  the  blood.  Later  experiments  of  Hedon 


*Ehrlich  found  the  glycogen  of  the  blood-leucocytes  to  be  markedly  in- 
creased in  amount  in  pancreatic  diabetes. 

**Kausch,  and  independently  Noel  Paton,  have  shown  that  removal  of  the 
pancreas  in  birds  does  not  as  a  rule  cause  glycosuria,  although  glycosuria  may 
be  present.  On  administering  adrenine,  glycosuria  is  at  once  produced. 


THE    PINEAL    GLAND,    THE   PANCREAS,   ETC.  85 

seem  to  show  that  the  autacoid  is  inactive  whilst  within  the  pancreatic 
vein,  and  only  becomes  activated  on  passing  through  the  liver. 

There  are  various  ways  in  which  the  prevention  of  an  undue  accumu- 
lation and  mobilization  of  glucose  and  the  consequent  appearance  of 
hyperglycaemia  might  be  supposed  to  be  effected  by  an  internal  secretion 
of  the  pancreas  islets: 

(1)  The  active  agent  may  itself  be  a  glycolytic  ferment   (Lepine) 
and  may  be  the  source  of  the  glycolytic  ferment  which  is  known  to  be 
present  in  blood.     If  so,  removal  or  disease  of  pancreas  would  tend  to 
produce  glycosuria  in  consequence  of  the  absence  of  sufficient  of  this 
ferment  to  effect  the  splitting  of  glucose,  so  that  the  sugar  of  the  body 
would  not  be  metabolized  further  and  would  be  passed  out  as  such  by  the 
urine.    As  against  this  theory  it  is  found  that  in  diabetes  the  glycolytic 
po\ver  of  the  blood  is  not  diminished,  and  although  in  support  of  it  the 
fact  has  been  urged  that  a  glycolytic  ferment  can  be  got  from  the  pan- 
creas it  must  be  pointed  out  that  this  is  by  no  means  peculiar  to  that 
organ,  for  a  similar  enzyme  is  yielded  by  most  organs  and  tissues  of 
the  body. 

(2)  It  may  be  of  the  nature  of  a  kinase,  the  function  of  which  is 
to  convert  a  pro-ferment  into  ferment  or  perhaps  to  promote  the  activity 
of  an  already  existing  ferment  which  serves  to  break  down  the  molecule 
of  glucose  and  prepare  it  for  ultimate  oxidation  in  the  muscles,  liver, 
etc.     In  support  of  this  hypothesis  it  is  stated  by  0.  Cohnheim  that  a 
combination  of  muscle  juice  with  pancreas  juice  (obtained  from  the  cells 
by  hydraulic  pressure)  is  far  more  active  glycolytically  than  either  of 
the  two  employed  singly;  although,  as  Levene  points  out,  the  disappear- 
ance of  sugar  which  is  caused  cannot  be  definitely  regarded  as  glycolysis. 
According  to  de  Meyer,  a  glycolytic  pro-ferment  which  is  activated  by 
insuline  is  contained  in  the  blood-leucocytes.    Anything  which  tends  to 
prevent  the  formation  of  insuline,  such  as  disease  of  the  islet- tissue  (and 
perhaps  the  entire  removal  of  the  pancreas),  the  action  of  adrenine 
would  therefore  necessarily  interfere  with  the  glycolysis  and  prevent 
the  utilization  of  glucose  by  the  tissues,  so  that  hyperglycaemia  and  gly- 
cosuria would  be  produced.     According  to  this  theory,  the  tissues  of  a 
depancreatized  dog  should  be  unable  or  less  able  to  utilize  glucose  for 
the  production  of  muscular  work.     Experiments  on  heart  muscle  which 
seemed  to  support  this  have  been  published  by  Knowlton  and  Starling. 
But  other  experiments  by  Forges  and  Salomon  (on  skeletal  muscle)  gave 
a  contrary  result,  and  Starling  has  since  come  to  the  conclusion  that  his 
results  with  Knowlton  were  within  the  limits  of  individual  variations  of 
the  normal  heart  muscle. 


86  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

(3)  The  substance  (insuline)  produced  by  the  pancreas  islets  may  be 
a  chalonic  autacoid  which  tends  to  inhibit  the  formation  of  glucose  from 
glycogen,  and  incidentally  to  promote  the  storage  of  glyeogen,  so  that  in 
its  absence  the  glycogen  which  is  present  in  the  liver  is  rapidly  con- 
verted into  glucose  and  the  sugar  absorbed  from  the  alimentary  canal  or 
found  in  the  body  is  not  stored  by  the  liver.  The  result  again  will  b*. 
hyperglycagmia  and  glycosuria.  The  fact  that  the  conversion  of  glycogen 
into  glucose  occurs  rapidly  in  the  excised  liver  seems  to  indicate  that  there 
is  something  which  under  ordinary  circumstances  acts  as  an  inhibitory 
agent,  and  we  may  well  suppose  this  to  be  yielded  to  the  blood  by  the 
pancreas. 

The  hypothesis  that  there  exists  a  chalonic  or  inhibitory  agent  in  the  in- 
ternal secretion  of  the  pancreas  which  affects  carbohydrate  metabolism  is  prob- 
ably the  correct  one;  but  whether  this  is  of  the  nature  of  an  autacoid  or  of  an 
enzyme  cannot  be  definitely  stated,  although  the  supposition  that  it  is  an  auta- 
coid is  most  in  accordance  with  what  is  known  regarding  the  effective  agents 
of  other  internal  secretions. 

Relation  of  internal  secretion  of  pancreas  to  other  endocrine  agents. — 
Hyperglycoemia  is  produced  not  only  by  extirpation  of  the  pancreas  but 
also  by  Bernard's  ring  or  puncture  of  the  medulla  oblongata,  by  stimula- 
tion of  the  splanchnics,  and  by  the  introduction  of  an  excess  of  adren- 
ine  into  the  blood.  That  the  last  named  acts  in  part  at  least  by  inhibit- 
ing the  internal  secretion  of  the  pancreas  is  suggested  by  the  result  of  its 
local  application,  but  there  is  no  doubt  that  its  main  action  is  on  the  twin 
cells  or  on  their  sympathetic  endsubstance.  In  fasting  animals  adrenine 
causes  disappearance  of  glycogen  from  the  liver  and  eventually  from  the 
muscles.  Repeated  doses  in  the  rabbit,  although  producing  further  gly- 
cosuria, may,  singular  to  relate,  be  accompanied  by  a  storage  of  gly- 
cogen in  the  liver.  Since  this  condition  is  accompanied  by  increase  of 
nitrogen  in  the  urine,  it  seems  certain  that  the  carbohydrate  has  now 
been  formed  from  the  disintegration  of  protein.  We  have  further  seen 
that  the  sugar-puncture  of  the  medulla  oblongata  is  not  effective  after 
removal  of  the  suprarenal  (nor,  according  to  Gushing,  after  extirpation 
of  the  pituitary)  and  probably  acts  through  these  organs.  Removal  of 
the  thyroid  prevents,  whilst  removal  of  the  parathyroids  facilitates,  both 
pancreatic  and  bulbar  glycoemia  and  glycosuria.  The  thyroid  autacoid 
may  therefore  be  regarded  as  antagonistic  to  that  of  the  pancreas,  whilst 
the  parathyroid  assists  it. 

We  have  seen  that  brushing  the  pancreas  with  adrenine  provokes 
marked  hyperglycasmia  and  glycosuria  and  that  this  is  not  merely  due  to 
absorption  of  the  autacoid  into  the  general  circulation  is  shown  by  the 
fact  that  the  excess  of  sugar  is  far  greater  than  when  other  organs  are 


THE    PINEAL   GLAND,    THE   PANCREAS,   ETC.  87 

so  treated.  It  is  not,  however,  only  through  the  pancreas  that  adrenine- 
glycosuria  is  produced,  for  it  has  been  shown  by  various  observers  that 
there  is  an  increase  of  sugar  in  depancreatized  animals,  and  also  in  cases 
of  diabetes  in  man  (Paton),  as  the  result  of  adrenine  injection.  More- 
over, the  effect  of  adrenine  is  produced  immediately  both  in  normal  and 
in  depancreatized  animals,  whereas  it  takes  some  hours  for  the  effect  of 
depancreatization  upon  carbohydrate  metabolism  to  show  itself.  On  the 
other  hand,  Zuelzer  and  others  have  found  that  adrenine-glycosuria  is 
prevented  by  pancreas  extracts  and  even  by  pancreatic  juice:  the  effect 
is,  however,  according  to  de  Meyer,  not  due  to  an  antagonizing  autacoid, 
but  to  the  effect  of  the  extracts  upon  the  permeability  of  the  kidney  for 
sugar.  The  result  of  administering  pilocarpine,  which  produces  marked 
secretion  from  the  pancreas  by  exciting  the  secreting  endings  of  the 
vagi,  is  also  to  prevent  adrenine-glycosuria :  possibly  it  acts  by  stimulat- 
ing the  nerve-endings  to  the  islet-cells.  An  increased  tolerance  to  sugar 
is  associated  with  diminished  activity  of  thyroid,  pituitary  (posterior 
lobe)  and  suprarenal  (medulla)  :  a  diminished  tolerance  with  the  oppo- 
site condition  of  these  glands.  According  to  Eppinger,  there  is  mutual 
inhibition  between  the  activity  of  the  autacoid  of  the  pancreas  which 
affects  carbohydrate  metabolism  and  those  of  the  thyroid  and  supra- 
renals :  whereas  the  two  last  named  mutually  assist  one  another.  Accord- 
ing to  Falta  and  Eudinger,  thyroid  and  parathyroid  are  mutually 
opposed  in  their  effect  upon  sympathetic  nerve-endings  and  through 
these  upon  carbohydrate  metabolism  as  influenced  by  the  suprarenals  and 
pancreas. 

It  will  be  seen  from  the  above  that  the  whole  question  of  the  mode  of 
production  of  pancreatic  diabetes  is  greatly  in  need  of  further  elucidation.  It 
would  appear,  however,  that,  apart  from  the  liver,  which  is  the  chief  stockhouse 
for  carbohydrates,  a  number  of  organs  are  concerned  in  governing  the  metabolism 
and  mobilization  of  carbohydrates,  all  being  more  or  less  interdependent.  Of 
these  organs  the  pancreas,  with  its  internal  secretion,  occupies  a  central 
position. 

THE  INTERNAL  SECRETIONS  OF  THE  GENERATIVE  GLANDS. 

1.  In  the  male  sex. — It  was  shown  by  Leydig  in  1850  that  the  inter- 
tubular  connective  tissue  of  the  testicle  is  characterized  by  the  presence 
of  strands  of  epithelium-like  cells ;  these  have  been  termed  the  ' '  cells  of 
Leydig,"  and,  collectively,  "the  interstitial  gland"  of  the  testis.  This 
varies  in  development  in  different  species  of  animals,  being  very  well 
marked  in  the  cat,  less  so  in  the  dog  and  mouse,  and  still  less  in  the  rat 
and  rabbit  and  in  man.  It  is,  however,  nearly  always  present  to  some 
extent,  and  Tandler  and  Grosz  have  shown  that  in  animals  which  undergo 


88  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

seasonal  changes  in  sexual  activity  the  interstitial  cells  may  be  even  better 
developed  when  the  seminiferous  tubules  are  inactive  than  during  the 
time  of  their  activity,  their  increased  development  generally  immediately 
preceding  that  of  the  seminiferous  epithelium.  The  tissue  may  also  be 
found  well  developed  in  cases  where  there  is  atrophy  of  the  contents  of 
the  seminiferous  tubules,  as  in  cases  of  cryptorchidism  and  after  liga- 
ture of  the  vas  def erens ;  although  if  the  whole  of  the  spermatic  cord  be 
included  in  the  ligature,  so  that  the  circulation  and  nerve  supply  to  the 
testicle  is  interfered  with,  the  interstitial  cells  may  share  in  the  general 
atrophy  of  the  organ  which  ensues. 

These  interstitial  cells  are  polygonal  in  shape  with  spherical  excentric 
nuclei,  a  well-marked  nucleolus  and  a  double  centrosome.  The  cytoplasm 
often  contains  lipoid  granules  of  a  yellowish  colour,  which  are  blackened 
by  osmic  acid;  and  also  other  granules  of  protein  nature,  which  may  be 
either  oxyphil  or  basophil.  Frequently,  as  shown  by  Reinke,  there  are 
crystals  within  the  cells,  but  the  exact  nature  of  these  has  not  been 
determined. 

Effects  of  castration. — The  results  of  removal  of  the  testes  are  well 
known.  If  the  operation  is  performed  in  the  child  the  secondary  sexual 
organs — especially  the  prostate  and  seminal  vesicles — remain  in  an  unde- 
veloped condition,  and  other  male  secondary  sexual  characters,  such  as 
the  growth  of  hair  on  the  face  and  pubes,  the  enlargement  of  the  larynx, 
and  the  development  of  the  male  characters  of  the  skeleton  are  arrested. 
In  such  animals  as  birds  and  deer,  in  which  the  external  characteristics 
of  the  male  sex  are  well  marked,  these  fail  to  show  themselves,  the  gen- 
eral features  of  development  approaching  those  usual  to  the  female  sex. 
As  Sellheim,  Geddes  and  others  have  shown,  modifications  occur  in  the 
growth  of  the  skeleton,  the  epiphyses  long  remaining  separate;  the  limb 
bones  are  longer  and  more  delicate  than  usual,  and  the  sutures  of  the 
skull  slower  in  ossifying.  The  mental  characteristics  also  undergo  altera- 
tion, tending  to  retain  a  more  infantile  type.  Most  of  the  ductless  glands 
are  affected,  the  thyroid  and  pituitary  being  diminished,  the  suprarenal 
cortex  and  thymus  increased  in  size:  the  last  named  organ  shows  arrest 
of  its  normal  retrogressive  changes.  If  castration  is  performed  in  the 
mature  animal,  and  therefore  after  the  secondary  sexual  characteristics 
have  become  developed,  there  may  be  some  retrogression  of  these,  and 
such  accessory  generative  glands  as  the  prostate  tend  to  undergo  atrophic 
changes.  But  the  effects  now  are  mainly  upon  metabolism,  shown  in  a 
tendency  to  increased  formation  of  fat,  although  the  limit  of  assimilation 
of  carbohydrates  is  lowered  and  alimentary  glycosuria  is  more  easily  pro- 


THE   PINEAL   GLAND,   THE  PANCREAS,  ETC.  89 

duced.    How  far  these  effects  on  metabolism  are  direct  or  how  far  indirect, 
through  the  ductless  glands,  it  is  not  possible  to  say. 

In  certain  animals  which  undergo  seasonal  variations  in  sexual  activity  the 
secondary  sexual  characters  which  generally  accompany  these  variations  are 
generally  also  abolished  or  modified  by  castration.  Thus  in  stags,  after 
castration,  the  antlers  either  remain  undeveloped  or  if  developed  are  shed 
prematurely  and  are  either  not  replaced  or  replaced  only  by  incomplete  growths. 
But  structures  which  are  common  to  both  sexes — where,  for  instance,  both 
possess  horns — are  not  modified  by  castration.  In  Arthropoda  this  correla- 
tion between  the  generative  glands  and  the  secondary  sexual  characters  (which 
in  many  species  are  even  more  marked  than  in  Vertebrata)  does  not  hold  good. 
Experiments  upon  caterpillars  show  that  removal  of  the  generative  glands 
has  no  influence  on  the  development  of  the  male  sexual  characters  of  the  imago ; 
nor  do  the  glands,  if  transplanted  into  individuals  of  the  other  sex,  affect  the 
secondary  sexual  characters  or  instincts  of  the  host.  This  need  not  be  taken 
to  mean  that  the  secondary  sexual  characters  in  these  animals  are  not  the  re- 
sult of  an  internal  secretion,  but  may  be  interpreted  by  supposing  that  some 
organ  other  than  the  generative  glands  furnishes  the  internal  secretion  which 
produces  those  characters. 

In  Vertebrata,  at  any  rate,  there  can  be  little  doubt  that  the  internal  secre- 
tions of  the  generative  glands  are  an  important  if  not  the  chief  factor  in  deter- 
mining the  development  of  the  secondary  sexual  characters.  And  that  this 
development  is  independent  of  the  normal  functions  of  the  generative  glands 
is  shown  by  the  fact  that  the  ligature  of  the  vas  deferens  has  no  effect  in  pre- 
venting it.  Moreover,  transplanted  testes  and  even  portions  of  the  testis  have 
been  found  capable  (in  birds)  of  preventing  the  results  of  castration:  the  comb, 
wattles,  spurs,  etc.,  of  the  cock  being  developed  in  the  usual  way.  Nussbaum's 
experiments  on  the  effect  upon  the  development  of  the  thumb-pad  of  grafting 
pieces  of  testis  from  another  frog  into  the  dorsal  lymph  sac  of  a  castrated  male 
frog  also  point  to  the  existence  of  an  internal  secretion  of  the  testicles  in  these 
animals. 

It  seems  certain,  therefore,  that  the  development  of  the  secondary 
sexual  characters  in  the  male  sex  is  dependent  upon  an  internal  secre- 
tion of  the  testicle  and  it  is  highly  probable  that  it  is  yielded  by  the 
interstitial  epithelium.  This  is  indicated  by  various  facts.  In  crypt- 
orchids,  and  also  after  experimental  ligature  of  the  vas  deferens,  in  both 
of  which,  as  we  have  seen,  the  seminiferous  epithelium  is  atrophied  but 
the  interstitial  tissue  is  well  developed,  the  secondary  sexual  characters 
and  sexual  desire  are  normal.  Successful  implantation  of  the  whole  or 
part  of  a  testicle  in  a  young  castrated  apimal  is  also  followed  by  develop- 
ment of  those  characters,  although  in  many  cases  the  seminiferous  epi- 
thelium of  the  graft  disappears.  Bouin  and  Ancel  state  that  extract  of 
testicle  freed  from  all  morphological  elements  may,  when  injected,  pro- 
duce a  similar  result.  In  support  of  the  theory  that  the  autacoid  which 
affects  the  development  of  the  secondary  sexual  organs  and  characters  is 


90  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

formed  by  the  interstitial  cells  they  have  found  that  if  one  testicle  be 
removed  from  a  rabbit  and  the  remaining  one  have  its  vas  ligatured  its 
interstitial  tissue  becomes  hypertrophied.  Further,  it  is  known  that  if 
the  testicles  be  treated  by  X-rays  the  seminiferous  epithelium  undergoes 
degeneration,  although  the  interstitial  tissue  is  not,  at  first  at  any  rate, 
attacked.  Young  animals  so  treated  develop  normal  secondary  sexual 
characters.  On  the  other  hand,  remarkable  cases  have  been  described, 
in  both  male  and  female  sex,  in  which  tumours  of  the  testicle  and  ovary 
apparently  malignant  in  character  occurring  in  children  have  been 
accompanied  by  a  general  growth  of  stature  and  by  premature  appear- 
ance of  secondary  sexual  characters,  such  as  growth  of  hair  on  the  face 
in  the  male  and  in  the  armpits  and  on  the  pubes  in  both  sexes,  develop- 
ment of  breasts  and  external  generative  organs :  in  short,  all  the  signs  of 
puberty;  which,  on  removal  of  the  tumour,  have  been  found  to  disap- 
pear. These  seem  to  be  cases  of  tumour  cells  taking  on  the  functions  of 
the  normal  cells  from  which  they  have  developed  (see  Lecture  II). 

2.  In  the  female  sex. — The  ovary  contains  besides  the  Graafian  follic- 
ies  with  their  ova,  follicular  epithelium  and  liquor  folliculi,  a  highly  vas- 
cular stroma  formed  of  a  peculiar  connective  tissue,  firm  in  texture  and 
containing  numerous  spindle-shaped  cells.  In  some  animals  it  is  possible 
to  discover  in  the  stroma  groups  of  cells  of  a  different  appearance  from 
that  of  the  ordinary  stroma  cells.  These  have  been  named  the  "intersti- 
tial cells ' '  of  the  ovary  and  have  been  by  some  thought  to  be  analogous  to 
the  interstitial  cells  of  the  testicle.  But  the  evidence  in  favour  of  this  sup- 
position is  far  from  conclusive.  There  are  also  formed  during  the  period 
of  sexual  activity — i.  e.  the  period  when  Graafian  follicles  are  undergoing 
maturation,  with  eventual  extrusion  of  the  contained  ova  and  liquor  fol- 
liculi and  of  part  of  the  follicular  epithelium — the  so-called  corpora  lutea. 
These  are  developments  of  the  burst  follicles,  but  their  full  development 
only  occurs  if  pregnancy  takes  place :  otherwise  the  corpus  luteum  after 
undergoing  a  certain  amount  of  development  becomes  the  subject  of  retro- 
gressive changes  and  presently  atrophies  and  disappears.  But  in  the  event 
of  pregnancy  occurring  important  changes  take  place  both  in  the  follicu- 
lar epithelium  which  remains  in  the  burst  follicle,  and  in  the  vascular 
wall  of  the  follicle  (theca)  which  is  derived  from  the  ovarian  stroma. 
The  follicular  epithelium  proliferates  and  the  individual  cells  become 
greatly  enlarged  and  filled  with  lipoid  granules  (which  give  the  yellow- 
ish colour  from  which  the  name  corpus  luteum  is  derived),  whilst  the 
inner  layer  of  the  theca  also  exhibits  proliferation  of  its  cells,  and  these, 
along  with  the  bloodvessels,  grow  in  amongst  the  luteal  cells  derived  from 
the  follicular  epithelium.  Thus  the  corpus  luteum  becomes  vascularized 


THE   PINEAL   GLAND,    THE   PANCREAS,   ETC.  91 

and  also  provided  with  a  framework  of  connective  tissue,  which  extends 
towards  the  scar  formed  where  the  follicle  originally  burst,  in  the  form 
of  a  central  strand  from  which  in  sections  columns  of  luteal  cells  appear 
to  radiate. 

The  corpus  luteum  is  well  marked  throughout  pregnancy,  although 
towards  the  end  it  becomes  less  sharply  defined  from  the  ovarian  stroma ; 
its  cells  tending  to  diffuse  into  this  and  eventually  losing  their  character- 
istic features.  Similar  changes  occur — but  with  far  less  increase  in  size — 
in  burst  follicles  where  pregnancy  has  not  supervened.  The  corpora  lutea 
thus  produced  have  been  termed  corpora,  lutea  spuria  to  distinguish  them 
from  the  corpura  lutea  vera  of  pregnancy.  But  the  mode  of  formation 
and  of  disappearance  seems  to  be  similar,  although  occurring  sooner.  It 
seems  not  improbable  that  it  is  some  of  the  cells  derived  from  previous 
corpora  lutea  that  have  been  described  by  various  observers  as  inter- 
stitial epithelial  cells,  for  the  cells  so  described  closely  resemble  luteal 
cells,  and  in  some  animals  groups  of  cells  derived  from  corpora  lutea 
which  have  disappeared  remain  a  long  time  visible  within  the  stroma. 

Effects  of  spaying.  The  effects  resulting  from  removal  of  both 
ovaries  (ob'phorectomy ;  spaying}  are  not  so  marked  externally  as  in  the 
similar  operation  in  the  male  sex.  If  performed  in  young  animals,  or  if 
the  ovaries  are  congenitally  atrophic,  it  is  not  infrequently  found  that 
characters  distinctive  to  the  male  are  to  some  extent  assumed.  In  the 
human  subject,  as  well  as  in  animals,  a  constant  result  is  that  the  uterus 
remains  small:  the  external  changes  characteristic  of  puberty  either  do 
not  occur  or  are  greatly  modified:  there  is  no  sign  of  menstruation.  A 
tendency  to  the  male  type  of  trichosis  is  often  also  exhibited.  When  the 
operation  is  performed  subsequent  to  puberty  the  results  are  less 
marked — but  menstruation  ceases  and  there  is  sometimes  atrophy  of  the 
breasts ;  in  animals  a  diminution  in  size  of  the  uterus  and  Fallopian  tubes 
has  been  substantiated.  Metabolism  is  affected  mainly  as  in  males  in  the 
direction  of  a  tendency  towards  adiposity.  This,  however,  may  be  indirect 
and  through  the  ductless  glands,  which  are  affected  much  in  the  same 
way  as  in  the  male  sex  by  removal  of  the  testicles. 

Doubtless,  as  in  the  male  sex,  the  effects  which  are  produced  by  the 
ovaries  in  determining  the  female  secondary  sexual  characters  are  due  to 
an  internal  secretion.  And  reasoning  from  analogy  one  would  be  dis- 
posed to  refer  the  production  of  this  not  to  the  generative  epithelium  but 
to  special  cells  in  the  ovarian  stroma.  Some  authorities  have  looked  upon 
the  so-called  interstitial  cells  in  this  light  and  have  supposed  that  they 
correspond  with  those  of  the  testicle  both  morphologically  and  physiolog- 
ically. 


92  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

They  are,  however,  affected  by  the  X-rays,  whilst  those  of  the  tes-. 
tide  are  not,  and,  as  we  have  seen,  they  show,  when  present,  many  anal- 
ogies with  the  cells  of  the  corpora  lutea.  The  latter  at  any  rate  appear 
not  to  be  concerned  with  the  secondary  sexual  phenomena,  for  it  has 
been  shown  that  heat  in  animals  will  still  occur  if  the  corpura  lutea  are 
destroyed,  or  if  none  are  present  in  the  ovary.  Moreover,  the  changes 
which  follow  spaying  can  be  prevented  by  ovarian  grafts  and  these  may 
contain  no  corpora  lutea.  The  grafts  may  also  show  after  a  time  no 
Graafian  follicles — these  having  undergone  degeneration  and  disappear- 
ance. This  is  not,  however,  a  necessary  consequence  of  reimplantation, 
for  instances  are  recorded  of  pregnancy  supervening  after  reimplanta- 
tion of  ovaries  in  spayed  animals.  Such  an  occurrence  has  been  reported 
in  the  case  of  a  woman  by  Halliday  Groom.  But  even  in  the  absence  of 
Graafian  follicles  from  the  implanted  ovarian  tissue,  Marshall  and  Jolly 
and  Mcllroy  have  shown  that  the  atrophic  changes  in  the  uterus  which 
ordinarily  follow  spaying  are  prevented.  It  would  seem,  therefore,  that 
the  cells  of  the  ovarian  stroma,  not  the  generative  cells,  are  the  source  of 
the  autacoids  which  maintain  the  nutrition  and  integrity  of  the  uterus 
and  produce  the  secondary  sexual  characters;  but  it  cannot  be  stated 
definitely  which  are  the  cells  of  the  stroma  that  give  rise  to  these  auta- 
coids. It  is  possible  that  the  so-called  interstitial  cells  may  so  act;  but, 
as  we  have  seen,  these  are  not  recognizable  as  distinct  structures  in 
all  animals. 

Steinach  has  found  that  implantation  of  ovaries  into  young  castrated  male 
rats  and  guineapigs  causes  the  appearance  of  certain  secondary  characters 
which  are  essentially  feminine,  including  hyperplasia  of  mammae  and  secre- 
tion of  milk.  And  similarly  he  obtained  secondary  male  characters  in  spayed 
females  in  which  he  succeeded  in  implanting  testicles. 

Internal  secretion  of  the  corpora  lutea. — That  the  corpora  lutea  have 
some  internally  secreting  function  is  highly  probable.  Their  epithelium 
is  distinctively  glandular  in  appearance  and  their  vascularity  suggests 
that  whatever  is  produced  within  them  is  passed  directly  into  the  blood. 
Th.  Sack  found  that  if  corpus  luteum  be  added  to  the  food  of  white  rats 
it  promotes  retention  of  nitrogen,  i.  e.  laying  on  of  flesh,  in  females  but 
not  in  males.  That  corpora  lutea  are  related  to  the  development  of  the 
mammary  gland  during  pregnancy  appears  from  the  experiments  of 
Ancel  and  Bouin  and  of  O'Donoghue,  who  have  found  that  if  in  the 
virgin  rabbit  a  Graafian  follicle  be  ruptured  (even  by  mechanical  means) 
so  that  a  corpus  luteum  develops,  the  mammae  undergo  evolution ;  whereas 
if  a  corpus  luteum  fails  to  form  there  is  no  such  evolution.  Hammond 
and  Marshall  find  that  under  these  circumstances  the  development  of  the 
mammae  may  even  proceed  so  far  as  to  produce  free  secretion  of  milk. 


THE   PINEAL   GLAND,   THE   PANCREAS,  ETC.  93 

The  development  of  corpora  lutea  in  non-pregnant  animals  is  also 
correlated  with  marked  uterine  hyperplasia.  Further,  extracts  of  corpus 
luteum  have  a  stimulating  effect  on  the  outpouring  of  the  secretion  of  the 
mammary  gland  only  second  in  activity  to  that  caused  by  extracts  of  the 
posterior  lobe  of  the  pituitary.  But  the  chief  function  of  its  internal 
secretion  seems  to  be  related  to  the  formation  of  the  uterine  decidua  and 
the  fixation  of  the  embryo.  Fraenkel — working  upon  a  hypothesis  sug- 
gested by  Born — found  that  if  in  mammals  the  corpora  lutea  are  de- 
stroyed at  an  early  period  of  pregnancy  the  embryo  does  not  become 
adherent  to  the  mucous  membrane  of  the  uterus  and  ceases  to  develop. 
L.  Loeb  has  observed  that  mechanical  stimuli  are  able  to  produce  the 
formation  of  decidual  membrane  if  corpora  lutea  are  present  in  the  ovary, 
but  that  there  is  no  such  formation  in  their  absence.  Extracts  of  corpus 
luteum  are  not  in  this  respect  able  to  replace  the  functions  of  the 
removed  organs.  Loeb  has  also  shown  that  in  the  guineapig  the  extir- 
pation accelerates  bursting  of  the  ripe  Graafian  follicles,  i.  e.  is  conducive 
to  ovulation;  from  this  it  may  be  deduced  that  their  presence  militates 
against  ovulation. 

It  is  further  stated  by  Ancel  and  Bouin  that  if  all  the  corpora  lutea 
are  destroyed  in  a  pregnant  rabbit  the  development  of  the  mammary 
gland  is  arrested,  and  it  is  inferred  that  their  secretion  is  necessary  for 
such  development.  It  must,  however,  be  stated  that  it  is  difficult  to 
destroy  all  the  corpora  lutea  in  a  rabbit's  ovary  without  practically  de- 
stroying all  the  ovarian  tissue,  for  the  corpora  lutea  of  the  pregnant 
rabbit  form  by  far  the  greater  mass  of  the  ovary. 

Internal  secretion  of  uterus. — There  is  some  evidence  that  in  certain 
states  the  uterus  itself  may  yield  an  internal  secretion.  Bouin  and  Ancel 
have  described  an  epithelial  formation  in  the  muscular  coat  of  the  uterus 
of  the  rabbit  and  guineapig  during  the  latter  half  of  pregnancy  which 
they  consider  to  be  related  to  the  development  of  the  mammary  glands 
during  the  final  period  of  gestation  and  the  production  of  milk.  To  this 
formation  they  have  given  the  name  of  " glande  myometricale  endocrine." 
Mackenzie  found  that  extracts  from  the  involuting  uterus  of  the  cat  after 
parturition  causes  a  free  flow  of  milk  from  the  incised  nipple  of  lactating 
animals.  He  obtained  no  such  results  with  extracts  made  either  from  the 
non-pregnant  uterus  except  shortly  after  parturition,  or  from  the  preg- 
nant uterus.  He  infers  therefore  that  the  uterus  contains  a  galactagogue 
hormone  only  at  this  period. 

Internal  secretion  of  mammary  gland. — A  similar  or  even  better 
marked  galactagogue  effect  was  obtained  by  Mackenzie  as  the  result  of 


94  ENDOCRINE  GLANDS  AND  INTERNAL  SECRETIONS 

intravenous  injection  of  extract  of  lactating  mammary  gland:  although 
no  result  is  obtained  from  the  gland  of  non-lactating  animals. 

Adler  states  that  subcutaneous  injection  of  the  extract  of  mammary 
gland  produces  enlargement  of  the  suprarenals  and  increase  of  adrenine 
in  the  blood,  sometimes  sufficient  to  cause  glycosuria.  He  also  i'uand  it 
to  arrest  the  development  of  the  embryo  and  even  to  produce  abortion  in 
pregnant  animals. 

Internal  secretion  of  the  placenta. — Various  observers  have  described 
experiments  which  seem  to  show  that  hypodermic  administration  of 
extract  of  placenta  or  feeding  with  placenta  produce  growth  of  the 
mammary  gland  and  an  increased  secretion  of  milk.  But  Mackenzie 
found  that,  so  far  from  the  latter  being  the  case,  injection  of  placental 
extract  tends  to  inhibit  the  effect  of  galactagogue  extracts  such  as  pitui- 
tary or  corpus  luteum.  A  similar  result  was  obtained  with  extract  of 
foetus,  which  has  also  been  thought  to  promote  mammary  development.  It 
would  seem  more  probable,  therefore,  that  both  placenta  and  foetus  pro- 
duce chalonic  autacoids  which  have  an  inhibitory  effect  on  milk  secretion ; 
and  as  a  commentary  on  this  it  may  be  noted  that  the  secretion  of  milk 
by  the  mammary  gland  does  not  begin  to  appear  until  the  removal 
of  any  influence  which  may  be  derived  from  them. 


\ 


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BIOLOGY  LIBRARY 


OCT  21  1932 
NOV  1  1932 


MOV 


AUG  27  1941 
OCT  1  4  1941 
NOV     21950 
JAN  101951 


LD  21-3m-6/32 


